Abstract:
To gain a better understanding of breast tumor angiogenesis, breast endothelial cells (ECs) were isolated and evaluated for gene expression patterns. When transcripts from breast ECs derived from normal and malignant breast tissues were compared, genes that were specifically elevated in tumor-associated breast endothelium were revealed. These results confirm that neoplastic and normal endothelium in human breast are distinct at the molecular level, and have significant implications for the development of anti-angiogenic therapies in the future.

Description:
TECHNICAL FIELD OF THE INVENTION 
       [0001]    This invention is related to the area of angiogenesis and anti-angiogenesis. In particular, it relates to genes which are characteristically expressed in breast tumor endothelial cells. 
       BACKGROUND OF THE INVENTION 
       [0002]    To date, global gene expression profiles from endothelial cell-specific populations is limited to normal and tumorigenic colon tissue [St Croix, 2000]. There is a need in the art for analysis of endothelial cells from other tissue, so that diagnostic and therapeutic agents for non-colonic tumors can be developed. 
       SUMMARY OF THE INVENTION 
       [0003]    According to one embodiment of the invention a method is provided to aid in diagnosing breast tumors. An expression product (protein or RNA) of at least one gene in a first breast tissue sample suspected of being neoplastic is detected. The at least one gene is selected from the group consisting of hypothetical protein DKFZp434G171; heat shock 70 kDa protein 1A; jagged 1 (Alagille syndrome); cyclin-dependent kinase 3; 6-phosphogluconolactonase; likely homolog of rat and mouse retinoid-inducible serine carboxypeptidase; plasmalemma vesicle associated protein; NADH:ubiquinone oxidoreductase MLRQ subunit homolog; HIF-1 responsive RTP801; ribosomal protein L27; secreted protein, acidic, cysteine-rich (osteonectin); hexokinase 1; ribosomal protein L13a; collagen, type IV, alpha 1; insulin-like growth factor binding protein 7; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); heat shock 10 kDa protein 1 (chaperonin 10); calcium channel, voltage-dependent, alpha 1H subunit; CD9 antigen (p24); TEM17; TEM13, Thy-1 cell surface antigen; Tax interaction protein 1; dysferlin, limb girdle muscular dystrophy 2B (autosomal recessive); hypothetical protein MGC34648; putative translation initiation factor; insulin-like growth factor binding protein 4; matrix metalloproteinase 9 (gelatinase B, 92 kDa gelatinase, 92 kDa type IV collagenase); heterogeneous nuclear ribonucleoprotein R; bHLH factor Hes4; collagen, type VI, alpha 2; T-box 2; glyceraldehyde-3-phosphate dehydrogenase; G protein-coupled receptor 4; collagen, type I, alpha 1; ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1); ribosomal protein, large, P1; TEM10, COL1A2 involved in tissue remodeling; heat shock 70 kDa protein 8; KIAA0152 gene product; Ca2+-promoted Ras inactivator; serine/arginine repetitive matrix 2; hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor); benzodiazapine receptor (peripheral); ectonucleoside triphosphate diphosphohydrolase 1; heparan sulfate proteoglycan 2 (perlecan); fibromodulin; hairy/enhancer-of-split related with YRPW motif 1; collagen, type V, alpha 3; hairy/enhancer-of-split related with YRPW motif-like; hypothetical protein MGC2731; amino-terminal enhancer of split; mitogen-activated protein kinase 9; regulator of G-protein signalling 5; prothymosin, alpha (gene sequence 28); tubulin, beta, 2; protease, serine, 23; hypothetical protein F1120898; calpain 1, (mu/I) large subunit; interferon, alpha-inducible protein (clone IFI-6-16); ESTs, Weakly similar to T25031 hypothetical protein T20D3.3— Caenorhabditis elegans [C. elegans ]; major histocompatibility complex, class I, C; hypoxia up-regulated 1; complement component 4B; prefoldin 2; cytoskeleton-associated protein 1; Rho GTPase activating protein 4;  Homo sapiens  clone FLC1492 PRO3121 mRNA, complete cds; transducin-like enhancer of split 2 (E(sp1) homolog,  Drosophila ); ribosomal protein L37; hypothetical protein MGC4677; ESTs, Highly similar to MT1A_HUMAN METALLOTHIONEIN-IA (MT-1A) [ H. sapiens ]; TEM11, nidogen (enactin); guanine nucleotide binding protein (G protein), gamma 5; matrix Gla protein; heat shock 105kD; GNAS complex locus;  Homo sapiens  cDNA FLJ11658 fis, clone HEMBA1004577; H19, imprinted maternally expressed untranslated mR NA; protein tyrosine phosphatase type IVA, member 3; snail homolog 1 ( Drosophila ); integrin-binding sialoprotein (bone sialoprotein, bone sialoprotein II); tissue inhibitor of metalloproteinase 1 (erythroid potentiating activity, collagenase inhibitor); peptidylprolyl isomerase B (cyclophilin B); MARCKS-like protein; FAST kinase; protease, serine, 11 (IGF binding); beta-2-microglobulin; delta sleep inducing peptide, immunoreactor; collagen, type IV, alpha 2; immediate early response 3; cadherin 5, type 2, VE-cadherin (vascular epithelium); RGC32 protein; guanylate cyclase 1, soluble, beta 3; major histocompatibility complex, class I, B; ribonuclease, RNase A family, 1 (pancreatic); collagen, type XVIII, alpha 1; v-jun sarcoma virus 17 oncogene homolog (avian);  Homo sapiens  mRNA; cDNA DKFZp686G1610 (from clone DKFZp686G1610); nucleolin; lectin, galactoside-binding, soluble, 3 binding protein; Lysosomal-associated multispanning membrane protein-5; ribosomal protein S16; guanine nucleotide binding protein (G protein), gamma 12; serine (or cysteine) proteinase inhibitor, Glade E (nexin, plasminogen activator inhibitor type 1), member 1; biglycan; DnaJ (Hsp40) homolog, subfamily B, member 1; tumor rejection antigen (gp96) 1; interferon, alpha-inducible protein (clo ne IFI-15K); solute carrier family 21 (prostaglandin transporter), member 2; CD74 antigen (invariant polypeptide of major histocompatibility complex, class II antigen-associated); serum/glucocorticoid regulated kinase; mitogen-activated protein kinase; receptor (calcitonin) activity modifying protein 3; sema domain, immunoglobulin domain (Ig); benzodiazapine receptor (peripheral)—mitochondrial; Cl domain-containing phosphatase &amp; tensin-like; and Notch homolog 3 ( Drosophila ). Expression of the at least one gene in the first breast tissue sample is compared to expression of the at least one gene in a second breast tissue sample which is normal. Increased expression of the at least one gene in the first breast endothelial tissue sample relative to the second tissue sample identifies the first breast tissue sample as likely to be neoplastic. 
         [0004]    According to another embodiment of the invention a method is provided of treating a breast tumor. Cells of the breast tumor are contacted with an antibody. The antibody specifically binds to an extracellular epitope of a protein selected from the group consisting of benzodiazapine receptor (peripheral); cadherin 5, type 2, VE-cadherin (vascular epithelium); calcium channel, voltage-dependent, alpha 1H subunit; CD74 antigen (invariant polypeptide of major histocompatibility complex, class II antigen-associated); CD9 antigen (p24); dysferlin, limb girdle muscular dystrophy 2B (autosomal recessive); ectonucleoside triphosphate diphosphohydrolase 1; G protein-coupled receptor 4; hypothetical protein F1120898; hypoxia up-regulated 1; immediate early response 3; interferon, alpha-inducible protein (clone IFI-6-16); jagged 1 (Alagille syndrome); KIAA0152 gene product; Lysosomal-associated multispanning membrane protein-5; major histocompatibility complex, class I, B; major histocompatibility complex, class I, C; NADH:ubiquinone oxidoreductase MLRQ subunit homolog; Notch homolog 3 ( Drosophila ); plasmalemma vesicle associated protein; solute carrier family 21 (prostaglandin transporter), member 2; TEM13, Thy-1 cell surface antigen; receptor (calcitonin) activity modifying protein 3; sema domain, immunoglobulin domain (Ig); benzodiazapine receptor (peripheral)—mitochondrial; and TEM17. Immune destruction of cells of the breast tumor is thereby triggered. 
         [0005]    According to still another embodiment of the invention a method is provided for identifying a test compound as a potential anti-cancer or anti-breast tumor drug. A test compound is contacted with a cell which expresses at least one gene selected from the group consisting of: hypothetical protein DKFZp434G171; heat shock 70 kDa protein 1A; jagged 1 (Alagille syndrome); cyclin-dependent kinase 3; 6-phosphogluconolactonase; likely homolog of rat and mouse retinoid-inducible serine carboxypeptidase; plasmalemma vesicle associated protein; NADH:ubiquinone oxidoreductase MLRQ subunit homolog; HIF-1 responsive RTP801; ribosomal protein L27; secreted protein, acidic, cysteine-rich (osteonectin); hexokinase 1; ribosomal protein L13a; collagen, type IV, alpha 1; insulin-like growth factor binding protein 7; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); heat shock 10 kDa protein 1 (chaperonin 10); calcium channel, voltage-dependent, alpha 1H subunit; CD9 antigen (p24); TEM17; TEM13, Thy-1 cell surface antigen; Tax interaction protein 1; dysferlin, limb girdle muscular dystrophy 2B (autosomal recessive); hypothetical protein MGC34648; putative translation initiation factor; insulin-like growth factor binding protein 4; matrix metalloproteinase 9 (gelatinase B, 92 kDa gelatinase, 92 kDa type IV collagenase); heterogeneous nuclear ribonucleoprotein R; bHLH factor Hes4; collagen, type VI, alpha 2; T-box 2; glyceraldehyde-3-phosphate dehydrogenase; G protein-coupled receptor 4; collagen, type I, alpha 1; ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1); ribosomal protein, large, P1; TEM10, COL1A2 involved in tissue remodeling; heat shock 70 kDa protein 8; KIAA0152 gene product; Ca2+-promoted Ras inactivator; serine/arginine repetitive matrix 2; hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor); benzodiazapine receptor (peripheral); ectonucleoside triphosphate diphosphohydrolase 1; heparan sulfate proteoglycan 2 (perlecan); fibromodulin; hairy/enhancer-of-split related with YRPW motif 1; collagen, type V, alpha 3; hairy/enhancer-of-split related with YRPW motif-like; hypothetical protein MGC2731; amino-terminal enhancer of split; mitogen-activated protein kinase 9; regulator of G-protein signalling 5; prothymosin, alpha (gene sequence 28); tubulin, beta, 2; protease, serine, 23; hypothetical protein F1120898; calpain 1, (mu/I) large subunit; interferon, alpha-inducible protein (clone IFI-6-16); ESTs, Weakly similar to T25031 hypothetical protein T20D3.3— Caenorhabditis elegans [C. elegans ]; major histocompatibility complex, class I, C; hypoxia up-regulated 1; complement component 4B; prefoldin 2; cytoskeleton-associated protein 1; Rho GTPase activating protein 4;  Homo sapiens  clone FLC1492 PRO3121 mRNA, complete cds; transducin-like enhancer of split 2 (E(sp1) homolog,  Drosophila ); ribosomal protein L37; hypothetical protein MGC4677; ESTs, Highly similar to MT1A_HUMAN METALLOTHIONEIN-IA (MT-1A) [ H. sapiens ]; TEM11, nidogen (enactin); guanine nucleotide binding protein (G protein), gamma 5; matrix Gla protein; heat shock 105kD; GNAS complex locus;  Homo sapiens  cDNA FLJ11658 fis, clone HEMBA1004577; H19, imprinted maternally expressed untranslated mR NA; protein tyrosine phosphatase type IVA, member 3; snail homolog 1 ( Drosophila ); integrin-binding sialoprotein (bone sialoprotein, bone sialoprotein II); tissue inhibitor of metalloproteinase 1 (erythroid potentiating activity, collagenase inhibitor); peptidylprolyl isomerase B (cyclophilin B); MARCKS-like protein; FAST kinase; protease, serine, 11 (IGF binding); beta-2-microglobulin; delta sleep inducing peptide, immunoreactor; collagen, type IV, alpha 2; immediate early response 3; cadherin 5, type 2, VE-cadherin (vascular epithelium); RGC32 protein; guanylate cyclase 1, soluble, beta 3; major histocompatibility complex, class I, B; ribonuclease, RNase A family, 1 (pancreatic); collagen, type XVIII, alpha 1; v-jun sarcoma virus 17 oncogene homolog (avian);  Homo sapiens  mRNA; cDNA DKFZp686G1610 (from clone DKFZp686G1610); nucleolin; lectin, galactoside-binding, soluble, 3 binding protein; Lysosomal-associated multispanning membrane protein-5; ribosomal protein S16; guanine nucleotide binding protein (G protein), gamma 12; serine (or cysteine) proteinase inhibitor, Glade E (nexin, plasminogen activator inhibitor type 1), member 1; biglycan; DnaJ (Hsp40) homolog, subfamily B, member 1; tumor rejection antigen (gp96) 1; interferon, alpha-inducible protein (clo ne IFI-15K); solute carrier family 21 (prostaglandin transporter), member 2; CD74 antigen (invariant polypeptide of major histocompatibility complex, class II antigen-associated); serum/glucocorticoid regulated kinase; mitogen-activated protein kinase; receptor (calcitonin) activity modifying protein 3; sema domain, immunoglobulin domain (Ig); benzodiazapine receptor (peripheral)—mitochondrial; Cl domain-containing phosphatase &amp; tensin-like; and Notch homolog 3 ( Drosophila ). An expression product of the at least one gene is monitored. The test compound is identified as a potential anti-cancer drug if it decreases the expression of the at least one gene. 
         [0006]    Still another embodiment of the invention is a method to induce an immune response to a breast tumor. A protein or nucleic acid encoding a protein is administered to a mammal, preferably a human. The protein is selected from the group consisting of: hypothetical protein DKFZp434G171; heat shock 70 kDa protein 1A; jagged 1 (Alagille syndrome); cyclin-dependent kinase 3; 6-phosphogluconolactonase; likely homolog of rat and mouse retinoid-inducible serine carboxypeptidase; plasmalemma vesicle associated protein; NADH:ubiquinone oxidoreductase MLRQ subunit homolog; HIF-1 responsive RTP801; ribosomal protein L27; secreted protein, acidic, cysteine-rich (osteonectin); hexokinase 1; ribosomal protein L13a; collagen, type IV, alpha 1; insulin-like growth factor binding protein 7; collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant); heat shock 10 kDa protein 1 (chaperonin 10); calcium channel, voltage-dependent, alpha 1H subunit; CD9 antigen (p24); TEM17; TEM13, Thy-1 cell surface antigen; Tax interaction protein 1; dysferlin, limb girdle muscular dystrophy 2B (autosomal recessive); hypothetical protein MGC34648; putative translation initiation factor; insulin-like growth factor binding protein 4; matrix metalloproteinase 9 (gelatinase B, 92 kDa gelatinase, 92 kDa type IV collagenase); heterogeneous nuclear ribonucleoprotein R; bHLH factor Hes4; collagen, type VI, alpha 2; T-box 2; glyceraldehyde-3-phosphate dehydrogenase; G protein-coupled receptor 4; collagen, type I, alpha 1; ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1); ribosomal protein, large, P1; TEM10, COL1A2 involved in tissue remodeling; heat shock 70 kDa protein 8; KIAA0152 gene product; Ca2+-promoted Ras inactivator; serine/arginine repetitive matrix 2; hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor); benzodiazapine receptor (peripheral); ectonucleoside triphosphate diphosphohydrolase 1; heparan sulfate proteoglycan 2 (perlecan); fibromodulin; hairy/enhancer-of-split related with YRPW motif 1; collagen, type V, alpha 3; hairy/enhancer-of-split related with YRPW motif-like; hypothetical protein MGC2731; amino-terminal enhancer of split; mitogen-activated protein kinase 9; regulator of G-protein signalling 5; prothymosin, alpha (gene sequence 28); tubulin, beta, 2; protease, serine, 23; hypothetical protein F1120898; calpain 1, (mu/I) large subunit; interferon, alpha-inducible protein (clone IFI-6-16); ESTs, Weakly similar to T25031 hypothetical protein T20D3.3— Caenorhabditis elegans [C. elegans ]; major histocompatibility complex, class I, C; hypoxia up-regulated 1; complement component 4B; prefoldin 2; cytoskeleton-associated protein 1; Rho GTPase activating protein 4;  Homo sapiens  clone FLC1492 PRO3121 mRNA, complete cds; transducin-like enhancer of split 2 (E(sp1) homolog,  Drosophila ); ribosomal protein L37; hypothetical protein MGC4677; ESTs, Highly similar to MT1A_HUMAN METALLOTHIONEIN-IA (MT-1A) [ H. sapiens ]; TEM11, nidogen (enactin); guanine nucleotide binding protein (G protein), gamma 5; matrix Gla protein; heat shock 105kD; GNAS complex locus;  Homo sapiens  cDNA FLJ11658 fis, clone HEMBA1004577; H19, imprinted maternally expressed untranslated mR NA; protein tyrosine phosphatase type IVA, member 3; snail homolog 1 ( Drosophila ); integrin-binding sialoprotein (bone sialoprotein, bone sialoprotein II); tissue inhibitor of metalloproteinase 1 (erythroid potentiating activity, collagenase inhibitor); peptidylprolyl isomerase B (cyclophilin B); MARCKS-like protein; FAST kinase; protease, serine, 11 (IGF binding); beta-2-microglobulin; delta sleep inducing peptide, immunoreactor; collagen, type IV, alpha 2; immediate early response 3; cadherin 5, type 2, VE-cadherin (vascular epithelium); RGC32 protein; guanylate cyclase 1, soluble, beta 3; major histocompatibility complex, class I, B; ribonuclease, RNase A family, 1 (pancreatic); collagen, type XVIII, alpha 1; v-jun sarcoma virus 17 oncogene homolog (avian);  Homo sapiens  mRNA; cDNA DKFZp686G1610 (from clone DKFZp686G1610); nucleolin; lectin, galactoside-binding, soluble, 3 binding protein; Lysosomal-associated multispanning membrane protein-5; ribosomal protein S16; guanine nucleotide binding protein (G protein), gamma 12; serine (or cysteine) proteinase inhibitor, Glade E (nexin, plasminogen activator inhibitor type 1), member 1; biglycan; DnaJ (Hsp40) homolog, subfamily B, member 1; tumor rejection antigen (gp96) 1; interferon, alpha-inducible protein (clo ne IFI-15K); solute carrier family 21 (prostaglandin transporter), member 2; CD74 antigen (invariant polypeptide of major histocompatibility complex, class II antigen-associated); serum/glucocorticoid regulated kinase; mitogen-activated protein kinase; receptor (calcitonin) activity modifying protein 3; sema domain, immunoglobulin domain (Ig); benzodiazapine receptor (peripheral)—mitochondrial; Cl domain-containing phosphatase &amp; tensin-like; and Notch homolog 3 ( Drosophila ). An immune response to the protein is thereby induced. 
         [0007]    The present invention thus provides the art with methods of diagnosing and treating breast tumors. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0008]    Using SAGE (Serial Analysis of Gene Expression) profiling, the present inventors were able to identify previously unrecognized, angiogenesis-specific markers that discriminate between non-proliferative and pathologic endothelial cells. In addition, a set of previously identified angiogenesis-specific markers from other tumor types (colon and/or brain) were found to be expressed in breast tumor endothelium as well. We identified 111 human genes that were expressed at significantly higher levels in breast tumor endothelium than in normal breast endothelium. See Table 1. Additional such genes which can be used similarly to the 11 human genes are shown in Table 2. We have named these markers BEMs (breast tumor endothelial markers). BEMs that are expressed in both colon and breast tumor epithelium are identified in Table 3. BEMs that are expressed in both brain and breast tumor epithelium are identified in Table 4. BEMs that are expressed in each of brain, colon, and breast tumor epithelium are identified in Table 5. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 111 Breast Markers 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.8728 
                 hypothetical protein 
                   
                 CAB61365 
               
               
                   
                 DKFZp434G171 
               
               
                 Hs.8997 
                 heat shock 70 kDa protein 1A 
                 140550 
                 NP_005336 
               
               
                 Hs.91143 
                 jagged 1 (Alagille syndrome) 
                 601920 
                 NP_000205 
               
               
                 Hs.100009 
                 cyclin-dependent kinase 3 
                 123828 
               
               
                 Hs.100071 
                 6-phosphogluconolactonase 
                 604951 
                 NP_036220 
               
               
                 Hs.106747 
                 likely homolog of rat and 
                   
                 NP_067639 
               
               
                   
                 mouse retinoid-inducible 
               
               
                   
                 serine carboxypeptidase 
               
               
                 Hs.107125 
                 plasmalemma vesicle 
                   
                 NP_112600 
               
               
                   
                 associated protein 
               
               
                 Hs.110024 
                 NADH: ubiquinone 
                   
                 NP_064527 
               
               
                   
                 oxidoreductase MLRQ subunit 
               
               
                   
                 homolog 
               
               
                 Hs.111244 
                 HIF-1 responsive RTP801 
                   
                 NP_061931 
               
               
                 Hs.111611 
                 ribosomal protein L27 
                 607526 
                 NP_000979 
               
               
                 Hs.111779 
                 secreted protein, acidic, 
                 182120 
                 NP_003109 
               
               
                   
                 cysteine-rich (osteonectin) 
               
               
                 Hs.118625 
                 hexokinase 1 
                 142600 
                 NP_277035 
               
               
                 Hs.119122 
                 ribosomal protein L13a 
               
               
                 Hs.119129 
                 collagen, type IV, alpha 1 
                 120130 
                 NP_001836 
               
               
                 Hs.119206 
                 insulin-like growth factor 
                 602867 
                 NP_001544 
               
               
                   
                 binding protein 7 
               
               
                 Hs.119571 
                 collagen, type III, alpha 1 
                 120180 
                 NP_000081 
               
               
                   
                 (Ehlers-Danlos syndrome 
               
               
                   
                 type IV, autosomal dominant) 
               
               
                 Hs.1197 
                 heat shock 10 kDa protein 1 
                 600141 
                 NP_002148 
               
               
                   
                 (chaperonin 10) 
               
               
                 Hs.122359 
                 calcium channel, voltage- 
                   
                 NP_066921 
               
               
                   
                 dependent, alpha 1H subunit 
               
               
                 Hs.1244 
                 CD9 antigen (p24) 
                 143030 
                 NP_001760 
               
               
                 Hs.125036 
                 TEM17 
                 606826 
                 NP_065138 
               
               
                 Hs.125359 
                 TEM13, Thy-1 cell surface 
                 188230 
                 NP_006279 
               
               
                   
                 antigen 
               
               
                 Hs.12956 
                 Tax interaction protein 1 
                   
                 NP_055419 
               
               
                 Hs.143897 
                 dysferlin, limb girdle 
                 603009 
                 NP_003485 
               
               
                   
                 muscular dystrophy 2B 
               
               
                   
                 (autosomal recessive) 
               
               
                 Hs.146360 
                 hypothetical protein MGC34648 
                   
                 NP_689873 
               
               
                 Hs.150580 
                 putative translation 
                   
                 NP_005792 
               
               
                   
                 initiation factor 
               
               
                 Hs.1516 
                 insulin-like growth factor 
                 146733 
                 NP_001543 
               
               
                   
                 binding protein 4 
               
               
                 Hs.151738 
                 matrix metalloproteinase 9 
                 120361 
                 NP_004985 
               
               
                   
                 (gelatinase B, 92 kDa 
               
               
                   
                 gelatinase, 92 kDa type IV 
               
               
                   
                 collagenase) 
               
               
                 Hs.15265 
                 heterogeneous nuclear 
                 607201 
                 NP_005817 
               
               
                   
                 ribonucleoprotein R 
               
               
                 Hs.154029 
                 bHLH factor Hes4 
                   
                 NP_066993 
               
               
                 Hs.159263 
                 collagen, type VI, alpha 2 
                 120240 
                 NP_001840 
               
               
                 Hs.168357 
                 T-box 2 
                 600747 
                 NP_005985 
               
               
                 Hs.169476 
                 glyceraldehyde-3-phosphate 
                 138400 
                 NP_002037 
               
               
                   
                 dehydrogenase 
               
               
                 Hs.17170 
                 G protein-coupled receptor 4 
                 600551 
                 NP_005273 
               
               
                 Hs.172928 
                 collagen, type I, alpha 1 
                 120150 
                 NP_000079 
               
               
                 Hs.173737 
                 ras-related C3 botulinum 
                 602048 
               
               
                   
                 toxin substrate 1 (rho family, 
               
               
                   
                 small GTP binding protein 
               
               
                   
                 Rac1) 
               
               
                 Hs.177592 
                 ribosomal protein, large, P1 
                 180520 
               
               
                 Hs.179573 
                 TEM10, COL1A2 involved in 
                 120160 
                 NP_000080 
               
               
                   
                 tissue remodeling 
               
               
                 Hs.180414 
                 heat shock 70 kDa protein 8 
                 600816 
                 NP_006588 
               
               
                 Hs.181418 
                 KIAA0152 gene product 
                   
                 NP_055545 
               
               
                 Hs.184367 
                 Ca2+-promoted Ras 
                   
                 BAA25464 
               
               
                   
                 inactivator 
               
               
                 Hs.197114 
                 serine/arginine repetitive 
                 606032 
                 NP_057417 
               
               
                   
                 matrix 2 
               
               
                 Hs.197540 
                 hypoxia-inducible factor 1, 
                 603348 
                 NP_001521 
               
               
                   
                 alpha subunit (basic helix- 
               
               
                   
                 loop-helix transcription 
               
               
                   
                 factor) 
               
               
                 Hs.202 
                 benzodiazapine receptor 
                 109610 
                 NP_000705 
               
               
                   
                 (peripheral) 
               
               
                 Hs.205353 
                 ectonucleoside triphosphate 
                 601752 
                 NP_001767 
               
               
                   
                 diphosphohydrolase 1 
               
               
                 Hs.211573 
                 heparan sulfate proteoglycan 
                 142461 
                 NP_005520 
               
               
                   
                 2 (perlecan) 
               
               
                 Hs.230 
                 Fibromodulin 
                 600245 
                 NP_002014 
               
               
                 Hs.234434 
                 hairy/enhancer-of-split 
                 602953 
                 NP_036390 
               
               
                   
                 related with YRPW motif 1 
               
               
                 Hs.235368 
                 collagen, type V, alpha 3 
                 120216 
                 NP_056534 
               
               
                 Hs.23823 
                 hairy/enhancer-of-split 
                   
                 NP_055386 
               
               
                   
                 related with YRPW motif-like 
               
               
                 Hs.240170 
                 hypothetical protein MGC2731 
                   
                 NP_076973 
               
               
                 Hs.244 
                 amino-terminal enhancer of 
                 600188 
               
               
                   
                 split 
               
               
                 Hs.246857 
                 mitogen-activated protein 
                 602896 
                 NP_620708 
               
               
                   
                 kinase 9 
               
               
                 Hs.24950 
                 regulator of G-protein 
                 603276 
                 NP_003608 
               
               
                   
                 signalling 5 
               
               
                 Hs.250655 
                 prothymosin, alpha (gene 
                 188390 
                 NP_002814 
               
               
                   
                 sequence 28) 
               
               
                 Hs.251653 
                 tubulin, beta, 2 
                 602660 
                 NP_006079 
               
               
                 Hs.25338 
                 protease, serine, 23 
               
               
                 Hs.25549 
                 hypothetical protein FLJ20898 
                   
                 NP_078876 
               
               
                 Hs.2575 
                 calpain 1, (mu/l) large 
                 114220 
                 NP_005177 
               
               
                   
                 subunit 
               
               
                 Hs.265827 
                 interferon, alpha-inducible 
                 147572 
                 NP_075011 
               
               
                   
                 protein (clone IFI-6-16) 
               
               
                 Hs.267200 
                 ESTs, Weakly similar to 
               
               
                   
                 T25031 hypothetical protein 
               
               
                   
                 T20D3.3 -  Caenorhabditis   
               
               
                   
                   elegans  [ C. elegans ] 
               
               
                 Hs.277477 
                 major histocompatibility 
                 142840 
                 NP_002108 
               
               
                   
                 complex, class I, C 
               
               
                 Hs.277704 
                 hypoxia up-regulated 1 
                 601746 
                 NP_006380 
               
               
                 Hs.278625 
                 complement component 4B 
                 120820 
                 NP_000583 
               
               
                 Hs.298229 
                 prefoldin 2 
                   
                 NP_036526 
               
               
                 Hs.31053 
                 cytoskeleton-associated 
                 601303 
                 NP_001272 
               
               
                   
                 protein 1 
               
               
                 Hs.3109 
                 Rho GTPase activating 
                 300023 
                 NP_001657 
               
               
                   
                 protein 4 
               
               
                 Hs.327412 
                   Homo sapiens  clone FLC1492 
               
               
                   
                 PRO3121 mRNA, complete cds 
               
               
                 Hs.332173 
                 transducin-like enhancer of 
                 601041 
                 NP_003251 
               
               
                   
                 split 2 (E(sp1) homolog, 
               
               
                   
                   Drosophila ) 
               
               
                 Hs.337445 
                 ribosomal protein L37 
                 604181 
                 NP_000988 
               
               
                 Hs.337986 
                 hypothetical protein MGC4677 
                   
                 NP_443103 
               
               
                 Hs.353882 
                 ESTs, Highly similar to 
               
               
                   
                 MT1A_HUMAN 
               
               
                   
                 METALLOTHIONEIN-IA 
               
               
                   
                 (MT-1A) [ H. sapiens ] 
               
               
                 Hs.356624 
                 TEM11, nidogen (enactin) 
                 131390 
                 NP_002499 
               
               
                 Hs.356668 
                 guanine nucleotide binding 
                 600874 
                 NP_005265 
               
               
                   
                 protein (G protein), gamma 5 
               
               
                 Hs.365706 
                 matrix Gla protein 
                 154870 
                 NP_000891 
               
               
                 Hs.36927 
                 heat shock 105 Kd 
                   
                 NP_006635 
               
               
                 Hs.374523 
                 GNAS complex locus 
                 139320 
                 NP_536350 
               
               
                 Hs.380824 
                   Homo sapiens  cDNA FLJ11658 
               
               
                   
                 fis, clone HEMBA1004577 
               
               
                 Hs.406410 
                 H19, imprinted maternally 
                 103280 
                 BAB71280 
               
               
                   
                 expressed untranslated mRNA 
               
               
                 Hs.43666 
                 protein tyrosine phosphatase 
                 606449 
                 NP_116000 
               
               
                   
                 type IVA, member 3 
               
               
                 Hs.48029 
                 snail homolog 1 ( Drosophila ) 
                 604238 
                 NP_005976 
               
               
                 Hs.49215 
                 integrin-binding sialoprotein 
                 147563 
                 NP_004958 
               
               
                   
                 (bone sialoprotein, bone 
               
               
                   
                 sialoprotein II) 
               
               
                 Hs.5831 
                 tissue inhibitor of 
                 305370 
                 NP_003245 
               
               
                   
                 metalloproteinase 1 (erythroid 
               
               
                   
                 potentiating activity, 
               
               
                   
                 collagenase inhibitor) 
               
               
                 Hs.699 
                 peptidylprolyl isomerase B 
                 123841 
                 NP_000933 
               
               
                   
                 (cyclophilin B) 
               
               
                 Hs.75061 
                 MARCKS-like protein 
                 602940 
                 NP_075385 
               
               
                 Hs.75087 
                 FAST kinase 
                 606965 
                 NP_079372 
               
               
                 Hs.75111 
                 protease, serine, 11 (IGF 
                 602194 
                 NP_002766 
               
               
                   
                 binding) 
               
               
                 Hs.75415 
                 beta-2-microglobulin 
                 109700 
                 NP_004039 
               
               
                 Hs.75450 
                 delta sleep inducing peptide, 
                 602960 
               
               
                   
                 immunoreactor 
               
               
                 Hs.75617 
                 collagen, type IV, alpha 2 
                 120090 
                 NP_001837 
               
               
                 Hs.76095 
                 immediate early response 3 
                 602996 
                 NP_434702 
               
               
                 Hs.76206 
                 cadherin 5, type 2, VE-cadherin 
                 601120 
                 NP_001786 
               
               
                   
                 (vascular epithelium) 
               
               
                 Hs.76640 
                 RGC32 protein 
               
               
                 Hs.77890 
                 guanylate cyclase 1, soluble, 
                 139397 
                 NP_000848 
               
               
                   
                 beta 3 
               
               
                 Hs.77961 
                 major histocompatibility 
                 142830 
                 NP_005505 
               
               
                   
                 complex, class I, B 
               
               
                 Hs.78224 
                 ribonuclease, RNase A family, 
                 180440 
                 AAH05324 
               
               
                   
                 1 (pancreatic) 
               
               
                 Hs.78409 
                 collagen, type XVIII, alpha 1 
                 120328 
                 NP_085059 
               
               
                 Hs.78465 
                 v-jun sarcoma virus 17 
                 165160 
                 NP_002219 
               
               
                   
                 oncogene homolog (avian) 
               
               
                 Hs.7869 
                   Homo sapiens  mRNA; cDNA 
               
               
                   
                 DKFZp686G1610 (from 
               
               
                   
                 clone DKFZp686G1610) 
               
               
                 Hs.79110 
                 Nucleolin 
                 164035 
                 NP_005372 
               
               
                 Hs.79339 
                 lectin, galactoside-binding, 
                 600626 
                 NP_005558 
               
               
                   
                 soluble, 3 binding protein 
               
               
                 Hs.79356 
                 Lysosomal-associated 
                 601476 
                 NP_006753 
               
               
                   
                 multispanning membrane 
               
               
                   
                 protein-5 
               
               
                 Hs.80617 
                 ribosomal protein S16 
                 603675 
               
               
                 Hs.8107 
                 guanine nucleotide binding 
               
               
                   
                 protein (G protein), gamma 12 
               
               
                 Hs.82085 
                 serine (or cysteine) 
                 173360 
                 NP_000593 
               
               
                   
                 proteinase inhibitor, clade E 
               
               
                   
                 (nexin, plasminogen activator 
               
               
                   
                 inhibitor type 1), member 1 
               
               
                 Hs.821 
                 Biglycan 
                 301870 
                 NP_001702 
               
               
                 Hs.82646 
                 DnaJ (Hsp40) homolog, 
                 604572 
                 NP_006136 
               
               
                   
                 subfamily B, member 1 
               
               
                 Hs.82689 
                 tumor rejection antigen 
                 191175 
                 NP_003290 
               
               
                   
                 (gp96) 1 
               
               
                 Hs.833 
                 interferon, alpha-inducible 
                 147571 
                 NP_005092 
               
               
                   
                 protein (clone IFI-15K) 
               
               
                 Hs.83974 
                 solute carrier family 21 
                 601460 
                 NP_005621 
               
               
                   
                 (prostaglandin transporter), 
               
               
                   
                 member 2 
               
               
                 Hs.84298 
                 CD74 antigen (invariant 
                 142790 
                 NP_004346 
               
               
                   
                 polypeptide of major 
               
               
                   
                 histocompatibility complex, 
               
               
                   
                 class II antigen-associated) 
               
               
                 Hs.8546 
                 Notch homolog 3 ( Drosophila ) 
                 600276 
                 NP_000426 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Additional Tumor Endothelial Markers in Breast 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.296323 
                 serum/glucocorticoid regulated 
                 602958 
                 NP_005618 
               
               
                   
                 kinase 
               
               
                 Hs.246857 
                 mitogen-activated protein 
                 602896 
                 NP_620708 
               
               
                   
                 kinase 
               
               
                 Hs.25691 
                 receptor (calcitonin) activity 
                 605155 
                 NP_005847 
               
               
                   
                 modifying protein 3 
               
               
                 Hs.9598 
                 sema domain, immunoglobulin 
                 — 
                 BAB21836 
               
               
                   
                 domain (Ig) 
               
               
                 Hs.202 
                 benzodiazapine receptor 
                 109610 
                 NP_000715 
               
               
                   
                 (peripheral) - mitochondrial 
               
               
                 Hs.6147 
                 C1 domain-containing 
                 — 
                 NP_056134 
               
               
                   
                 phosphatase &amp; tensin-like 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Markers in Colon and Breast Tumor Epithelium 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.8997 
                 heat shock 70 kDa protein 1A 
                 140550 
                 NP_005336 
               
               
                 Hs.110024 
                 NADH: ubiquinone 
                   
                 NP_064527 
               
               
                   
                 oxidoreductase MLRQ subunit 
               
               
                   
                 homolog 
               
               
                 Hs.111779 
                 secreted protein, acidic, 
                 182120 
                 NP_003109 
               
               
                   
                 cysteine-rich (osteonectin) 
               
               
                 Hs.119129 
                 collagen, type IV, alpha 1 
                 120130 
                 NP_001836 
               
               
                 Hs.119206 
                 insulin-like growth factor 
                 602867 
                 NP_001544 
               
               
                   
                 binding protein 7 
               
               
                 Hs.119571 
                 collagen, type III, alpha 1 
                 120180 
                 NP_000081 
               
               
                   
                 (Ehlers-Danlos syndrome type 
               
               
                   
                 IV, autosomal dominant) 
               
               
                 Hs.1197 
                 heat shock 10 kDa protein 1 
                 600141 
                 NP_002148 
               
               
                   
                 (chaperonin 10) 
               
               
                 Hs.125036 
                 TEM17 
                 606826 
                 NP_065138 
               
               
                 Hs.125359 
                 TEM13, Thy-1 cell surface 
                 188230 
                 NP_006279 
               
               
                   
                 antigen 
               
               
                 Hs.151738 
                 matrix metalloproteinase 9 
                 120361 
                 NP_004985 
               
               
                   
                 (gelatinase B, 92 kDa 
               
               
                   
                 gelatinase, 92 kDa type IV 
               
               
                   
                 collagenase) 
               
               
                 Hs.159263 
                 collagen, type VI, alpha 2 
                 120240 
                 NP_001840 
               
               
                 Hs.168357 
                 T-box 2 
                 600747 
                 NP_005985 
               
               
                 Hs.172928 
                 collagen, type I, alpha 1 
                 120150 
                 NP_000079 
               
               
                 Hs.179573 
                 TEM10, COL1A2 involved in 
                 120160 
                 NP_000080 
               
               
                   
                 tissue remodeling 
               
               
                 Hs.230 
                 Fibromodulin 
                 600245 
                 NP_002014 
               
               
                 Hs.23823 
                 hairy/enhancer-of-split 
                   
                 NP_055386 
               
               
                   
                 related with YRPW motif-like 
               
               
                 Hs.24950 
                 regulator of G-protein 
                 603276 
                 NP_003608 
               
               
                   
                 signalling 5 
               
               
                 Hs.265827 
                 interferon, alpha-inducible 
                 147572 
                 NP_075011 
               
               
                   
                 protein (clone IFI-6-16) 
               
               
                 Hs.327412 
                   Homo sapiens  clone FLC1492 
               
               
                   
                 PRO3121 mRNA, complete cds 
               
               
                 Hs.337986 
                 hypothetical protein 
                   
                 NP_443103 
               
               
                   
                 MGC4677 
               
               
                 Hs.356624 
                 TEM11, nidogen (enactin) 
                 131390 
                 NP_002499 
               
               
                 Hs.36927 
                 heat shock 105 kD 
                   
                 NP_006635 
               
               
                 Hs.43666 
                 protein tyrosine phosphatase 
                 606449 
                 NP_116000 
               
               
                   
                 type IVA, member 3 
               
               
                 Hs.5831 
                 tissue inhibitor of 
                 305370 
                 NP_003245 
               
               
                   
                 metalloproteinase 1 
               
               
                   
                 (erythroid potentiating 
               
               
                   
                 activity, collagenase 
               
               
                   
                 inhibitor) 
               
               
                 Hs.699 
                 peptidylprolyl isomerase B 
                 123841 
                 NP_000933 
               
               
                   
                 (cyclophilin B) 
               
               
                 Hs.75617 
                 collagen, type IV, alpha 2 
                 120090 
                 NP_001837 
               
               
                 Hs.77890 
                 guanylate cyclase 1, 
                 139397 
                 NP_000848 
               
               
                   
                 soluble, beta 3 
               
               
                 Hs.78409 
                 collagen, type XVIII, 
                 120328 
                 NP_085059 
               
               
                   
                 alpha 1 
               
               
                 Hs.78465 
                 v-jun sarcoma virus 17 
                 165160 
                 NP_002219 
               
               
                   
                 oncogene homolog (avian) 
               
               
                 Hs.821 
                 Biglycan 
                 301870 
                 NP_001702 
               
               
                 Hs.82646 
                 DnaJ (Hsp40) homolog, 
                 604572 
                 NP_006136 
               
               
                   
                 subfamily B, member 1 
               
               
                 Hs.8546 
                 Notch homolog 3 ( Drosophila ) 
                 600276 
                 NP_000426 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Markers in Brain and Breast Tumor Epithelium 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.107125 
                 plasmalemma vesicle associated 
                   
                 NP_112600 
               
               
                   
                 protein 
               
               
                 Hs.111611 
                 ribosomal protein L27 
                 607526 
                 NP_000979 
               
               
                 Hs.111779 
                 Secreted protein, acidic, 
                 182120 
                 NP_003109 
               
               
                   
                 cysteine-rich (osteonectin) 
               
               
                 Hs.119129 
                 Collagen, type IV, alpha 1 
                 120130 
                 NP_001836 
               
               
                 Hs.119571 
                 Collagen, type III, alpha 1 
                 120180 
                 NP_000081 
               
               
                   
                 (Ehlers-Danlos syndrome type 
               
               
                   
                 IV, autosomal dominant) 
               
               
                 Hs.125359 
                 TEM13, Thy-1 cell surface 
                 188230 
                 NP_006279 
               
               
                   
                 antigen 
               
               
                 Hs.143897 
                 Dysferlin, limb girdle 
                 603009 
                 NP_003485 
               
               
                   
                 muscular dystrophy 
               
               
                   
                 2B (autosomal recessive) 
               
               
                 Hs.151738 
                 matrix metalloproteinase 9 
                 120361 
                 NP_004985 
               
               
                   
                 (gelatinase B, 92 kDa 
               
               
                   
                 gelatinase, 92 kDa type IV 
               
               
                   
                 collagenase) 
               
               
                 Hs.159263 
                 Collagen, type VI, alpha 2 
                 120240 
                 NP_001840 
               
               
                 Hs.172928 
                 Collagen, type I, alpha 1 
                 120150 
                 NP_000079 
               
               
                 Hs.179573 
                 TEM10, COL1A2 involved in 
                 120160 
                 NP_000080 
               
               
                   
                 tissue remodeling 
               
               
                 Hs.211573 
                 Heparan sulfate proteoglycan 2 
                 142461 
                 NP_005520 
               
               
                   
                 (perlecan) 
               
               
                 Hs.277477 
                 major histocompatibility 
                 142840 
                 NP_002108 
               
               
                   
                 complex, class I, C 
               
               
                 Hs.327412 
                   Homo sapiens  clone FLC1492 
               
               
                   
                 PRO3121 mRNA, complete cds 
               
               
                 Hs.332173 
                 transducin-like enhancer of 
                 601041 
                 NP_003251 
               
               
                   
                 split 2 (E(sp1) homolog, 
               
               
                   
                   Drosophila ) 
               
               
                 Hs.337986 
                 hypothetical protein MGC4677 
                   
                 NP_443103 
               
               
                 Hs.365706 
                 matrix Gla protein 
                 154870 
                 NP_000891 
               
               
                 Hs.75061 
                 MARCKS-like protein 
                 602940 
                 NP_075385 
               
               
                 Hs.75111 
                 Protease, serine, 11 (IGF 
                 602194 
                 NP_002766 
               
               
                   
                 binding) 
               
               
                 Hs.75617 
                 collagen, type IV, alpha 2 
                 120090 
                 NP_001837 
               
               
                 Hs.77961 
                 major histocompatibility 
                 142830 
                 NP_005505 
               
               
                   
                 complex, class I, B 
               
               
                 Hs.79356 
                 Lysosomal-associated 
                 601476 
                 NP_006753 
               
               
                   
                 multispanning 
               
               
                   
                 membrane protein-5 
               
               
                 Hs.82085 
                 serine (or cysteine) 
                 173360 
                 NP_000593 
               
               
                   
                 proteinase inhibitor, 
               
               
                   
                 clade E (nexin, plasminogen 
               
               
                   
                 activator inhibitor type 1), 
               
               
                   
                 member 1 
               
               
                 Hs.821 
                 Biglycan 
                 301870 
                 NP_001702 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Breast, Brain, and Colon Tumor Endothelial Markers 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.111779 
                 secreted protein, acidic, 
                 182120 
                 NP_003109 
               
               
                   
                 cysteine-rich (osteonectin) 
               
               
                 Hs.119129 
                 collagen, type IV, alpha 1 
                 120130 
                 NP_001836 
               
               
                 Hs.119571 
                 collagen, type III, alpha 1 
                 120180 
                 NP_000081 
               
               
                   
                 (Ehlers-Danlos syndrome 
               
               
                   
                 type IV, autosomal 
               
               
                   
                 dominant) 
               
               
                 Hs.125359 
                 TEM13, Thy-1 cell surface 
                 188230 
                 NP_006279 
               
               
                   
                 antigen 
               
               
                 Hs.151738 
                 matrix metalloproteinase 9 
                 120361 
                 NP_004985 
               
               
                   
                 (gelatinase B, 92 kDa 
               
               
                   
                 gelatinase, 92 kDa type IV 
               
               
                   
                 collagenase) 
               
               
                 Hs.159263 
                 collagen, type VI, alpha 2 
                 120240 
                 NP_001840 
               
               
                 Hs.172928 
                 collagen, type I, alpha 1 
                 120150 
                 NP_000079 
               
               
                 Hs.179573 
                 TEM10, COL1A2 involved in 
                 120160 
                 NP_000080 
               
               
                   
                 tissue remodeling 
               
               
                 Hs.327412 
                   Homo sapiens  clone 
               
               
                   
                 FLC1492 PRO3121 mRNA, 
               
               
                   
                 complete cds 
               
               
                 Hs.337986 
                 hypothetical protein 
                   
                 NP_443103 
               
               
                   
                 MGC4677 
               
               
                 Hs.75617 
                 collagen, type IV, alpha 2 
                 120090 
                 NP_001837 
               
               
                 Hs.821 
                 biglycan 
                 301870 
                 NP_001702 
               
               
                   
               
             
          
         
       
     
         [0009]    Endothelial cells (ECs) represent only a minor fraction of the total cells within normal or tumor tissues, and only those EC transcripts expressed at the highest levels would be expected to be represented in libraries constructed from unfractionated tissues. The genes described in the current study should therefore provide a valuable resource for basic and clinical studies of human breast angiogenesis in the future. 
         [0010]    Isolated and purified nucleic acids, according to the present invention are those which are not linked to those genes to which they are linked in the human genome. Moreover, they are not present in a mixture such as a library containing a multitude of distinct sequences from distinct genes. They may be, however, linked to other genes such as vector sequences or sequences of other genes to which they are not naturally adjacent. 
         [0011]    The nucleic acids may represent either the sense or the anti-sense strand. Nucleic acids and proteins although disclosed herein with sequence particularity, may be derived from a single individual. Allelic variants which occur in the population of humans are included within the scope of such nucleic acids and proteins. Those of skill in the art are well able to identify allelic variants as being the same gene or protein. Given a nucleic acid, one of ordinary skill in the art can readily determine an open reading frame present, and consequently the sequence of a polypeptide encoded by the open reading frame and, using techniques well known in the art, express such protein in a suitable host. Proteins comprising such polypeptides can be the naturally occurring proteins, fusion proteins comprising exogenous sequences from other genes from humans or other species, epitope tagged polypeptides, etc. Isolated and purified proteins are not in a cell, and are separated from the normal cellular constituents, such as nucleic acids, lipids, etc. Typically the protein is purified to such an extent that it comprises the predominant species of protein in the composition, such as greater than 50, 60 70, 80, 90, or even 95% of the proteins present. 
         [0012]    Using the proteins according to the invention, one of ordinary skill in the art can readily generate antibodies which specifically bind to the proteins. Such antibodies can be monoclonal or polyclonal. They can be chimeric, humanized, or totally human. Any functional fragment or derivative of an antibody can be used including Fab, Fab′, Fab2, Fab′2, and single chain variable regions. So long as the fragment or derivative retains specificity of binding for the endothelial marker protein it can be used. Antibodies can be tested for specificity of binding by comparing binding to appropriate antigen to binding to irrelevant antigen or antigen mixture under a given set of conditions. If the antibody binds to the appropriate antigen at least 2, 5, 7, and preferably 10 times more than to irrelevant antigen or antigen mixture then it is considered to be specific. 
         [0013]    Techniques for making such partially to fully human antibodies are known in the art and any such techniques can be used. According to one particularly preferred embodiment, fully human antibody sequences are made in a transgenic mouse which has been engineered to express human heavy and light chain antibody genes. Multiple strains of such transgenic mice have been made which can produce different classes of antibodies. B cells from transgenic mice which are producing a desirable antibody can be fused to make hybridoma cell lines for continuous production of the desired antibody. See for example, Nina D. Russel, Jose R. F. Corvalan, Michael L. Gallo, C. Geoffrey Davis, Liise-Anne Pirofski. Production of Protective Human Antipneumococcal Antibodies by Transgenic Mice with Human Immunoglobulin Loci  Infection and Immunity  April 2000, p. 1820-1826; Michael L. Gallo, Vladimir E. Ivanov, Aya Jakobovits, and C. Geoffrey Davis. The human immunoglobulin loci introduced into mice: V (D) and J gene segment usage similar to that of adult humans  European Journal of Immunology  30: 534-540, 2000; Larry L. Green. Antibody engineering via genetic engineering of the mouse: XenoMouse strains are a vehicle for the  facile  generation of therapeutic human monoclonal antibodies  Journal of Immunological Methods  231 11-23, 1999; Yang X-D, Corvalan JRF, Wang P, Roy CM-N and Davis CG. Fully Human Anti-interleukin-8 Monoclonal Antibodies: Potential Therapeutics for the Treatment of Inflammatory Disease States.  Journal of Leukocyte Biology  Vol. 66, pp 401-410 (1999); Yang X-D, Jia X-C, Corvalan JRF, Wang P, CG Davis and Jakobovits A. Eradication of Established Tumors by a Fully Human Monoclonal Antibody to the Epidermal Growth Factor Receptor without Concomitant Chemotherapy.  Cancer Research  Vol. 59, Number 6, pp 1236-1243 (1999); Jakobovits A. Production and selection of antigen-specific fully human monoclonal antibodies from mice engineered with human Ig loci.  Advanced Drug Delivery Reviews  Vol. 31, pp: 33-42 (1998); Green L and Jakobovits A. Regulation of B cell development by variable gene complexity in mice reconstituted with human immunoglobulin yeast artificial chromosomes.  J. Exp. Med . Vol. 188, Number 3, pp: 483-495 (1998); Jakobovits A. The long-awaited magic bullets: therapeutic human monoclonal antibodies from transgenic mice.  Exp. Opin. Invest. Drugs  Vol. 7(4), pp: 607-614 (1998); Tsuda H, Maynard-Currie K, Reid L, Yoshida T, Edamura K, Maeda N, Smithies O, Jakobovits A. Inactivation of Mouse HPRT locus by a 203-bp retrotransposon insertion and a 55-kb gene-targeted deletion: establishment of new HPRT-Deficient mouse embryonic sBEM cell lines.  Genomics  Vol. 42, pp: 413-421 (1997); Sherman-Gold, R. Monoclonal Antibodies: The Evolution from &#39;80s Magic Bullets To Mature, Mainstream Applications as Clinical Therapeutics.  Genetic Engineering  News Vol. 17, Number 14 (August 1997); Mendez M, Green L, Corvalan J, Jia X-C, Maynard-Currie C, Yang X-d, Gallo M, Louie D, Lee D, Erickson K, Luna J, Roy C, Abderrahim H, Kirschenbaum F, Noguchi M, Smith D, Fukushima A, Hales J, Finer M, Davis C, Zsebo K, Jakobovits A. Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice.  Nature Genetics  Vol. 15, pp: 146-156 (1997); Jakobovits A. Mice engineered with human immunoglobulin YACs: A new technology for production of fully human antibodies for autoimmunity therapy.  Weir&#39;s Handbook of Experimental Immunology, The Integrated Immune System  Vol. IV, pp: 194.1-194.7 (1996); Jakobovits A. Production of fully human antibodies by transgenic mice.  Current Opinion in Biotechnology  Vol. 6, No. 5, pp: 561-566 (1995); Mendez M, Abderrahim H, Noguchi M, David N, Hardy M, Green L, Tsuda H, Yoast S, Maynard-Currie C, Garza D, BEMmill R, Jakobovits A, Klapholz S. Analysis of the structural integrity of YACs comprising human immunoglobulin genes in yeast and in embryonic sBEM cells.  Genomics  Vol. 26, pp: 294-307 (1995); Jakobovits A. YAC Vectors: Humanizing the mouse genome.  Current Biology  Vol. 4, No. 8, pp: 761-763 (1994); Arbones M, Ord D, Ley K, Ratech H, Maynard-Curry K, Otten G, Capon D, Tedder T. Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice.  Immunity  Vol. 1, No. 4, pp: 247-260 (1994); Green L, Hardy M, Maynard-Curry K, Tsuda H, Louie D, Mendez M, Abderrahim H, Noguchi M, Smith D, Zeng Y, et. al. Antigen-specific human monoclonal antibodies from mice engineered with human Ig heavy and light chain YACs.  Nature Genetics  Vol. 7, No. 1, pp: 13-21 (1994); Jakobovits A, Moore A, Green L, Vergara G, Maynard-Curry K, Austin H, Klapholz S. Germ-line transmission and expression of a human-derived yeast artificial chromosome.  Nature  Vol. 362, No. 6417, pp: 255-258 (1993); Jakobovits A, Vergara G, Kennedy J, Hales J, McGuinness R, Casentini-Borocz D, Brenner D, Otten G. Analysis of homozygous mutant chimeric mice: deletion of the immunoglobulin heavy-chain joining region blocks B-cell development and antibody production.  Proceedings of the National Academy of Sciences USA  Vol. 90, No. 6, pp: 2551-2555 (1993); Kucherlapati et al., U.S. Pat. No. 6,1075,181. 
         [0014]    Antibodies can also be made using phage display techniques. Such techniques can be used to isolate an initial antibody or to generate variants with altered specificity or avidity characteristics. Single chain Fv can also be used as is convenient. They can be made from vaccinated transgenic mice, if desired. Antibodies can be produced in cell culture, in phage, or in various animals, including but not limited to cows, rabbits, goats, mice, rats, hamsters, guinea pigs, sheep, dogs, cats, monkeys, chimpanzees, apes. 
         [0015]    Antibodies can be labeled with a detectable moiety such as a radioactive atom, a chromophore, a fluorophore, or the like. Such labeled antibodies can be used for diagnostic techniques, either in vivo, or in an isolated test sample. Antibodies can also be conjugated, for example, to a pharmaceutical agent, such as chemotherapeutic drug or a toxin. They can be linked to a cytokine, to a ligand, to another antibody. Suitable agents for coupling to antibodies to achieve an anti-tumor effect include cytokines, such as interleukin 2 (IL-2) and Tumor Necrosis Factor (TNF); photosensitizers, for use in photodynamic therapy, including aluminum (III) phthalocyanine tetrasulfonate, hematoporphyrin, and phthalocyanine; radionuclides, such as iodine-131 ( 131 I), yttrium-90 ( 90 Y), bismuth-212 ( 212 Bi), bismuth-213 ( 213 Bi), technetium-99m ( 99m Tc), rhenium-186 ( 186 Re), and rhenium-188 ( 188 Re); antibiotics, such as doxorubicin, adriamycin, daunorubicin, methotrexate, daunomycin, neocarzinostatin, and carboplatin; bacterial, plant, and other toxins, such as diphtheria toxin, pseudomonas exotoxin A, staphylococcal enterotoxin A, abrin-A toxin, ricin A (deglycosylated ricin A and native ricin A), TGF-alpha toxin, cytotoxin from chinese cobra (naja naja atra), and gelonin (a plant toxin); ribosome inactivating proteins from plants, bacteria and fungi, such as restrictocin (a ribosome inactivating protein produced by  Aspergillus restrictus ), saporin (a ribosome inactivating protein from  Saponaria officinalis ), and RNase; tyrosine kinase inhibitors; ly207702 (a difluorinated purine nucleoside); liposomes containing antitumor agents (e.g., antisense oligonucleotides, plasmids which encode for toxins, methotrexate, etc.); and other antibodies or antibody fragments, such as F(ab). 
         [0016]    Those of skill in the art will readily understand and be able to make such antibody derivatives, as they are well known in the art. The antibodies may be cytotoxic on their own, or they may be used to deliver cytotoxic agents to particular locations in the body. The antibodies can be administered to individuals in need thereof as a form of passive immunization. 
         [0017]    Characterization of extracellular regions for the cell surface and secreted proteins from the protein sequence is based on the prediction of signal sequence, transmembrane domains and functional domains. Antibodies are preferably specifically immunoreactive with membrane associated proteins, particularly to extracellular domains of such proteins or to secreted proteins. Such targets are readily accessible to antibodies, which typically do not have access to the interior of cells or nuclei. However, in some applications, antibodies directed to intracellular proteins may be useful as well. Moreover, for diagnostic purposes, an intracellular protein may be an equally good target since cell lysates may be used rather than a whole cell assay. 
         [0018]    Computer programs can be used to identify extracellular domains of proteins whose sequences are known. Such programs include SMART software (Schultz et al., Proc. Natl. Acad. Sci. USA 95: 5857-5864, 1998) and Pfam software (BaBEMan et al., Nucleic acids Res. 28: 263-266, 2000) as well as PSORTII. Typically such programs identify transmembrane domains; the extracellular domains are identified as immediately adjacent to the transmembrane domains. Prediction of extracellular regions and the signal cleavage sites are only approximate. It may have a margin of error + or −5 residues. Signal sequence can be predicted using three different methods (Nielsen et al,  Protein Engineering  10: 1-6,1997, Jagla et. al, Bioinformatics 16: 245-250, 2000, Nakai, K and Horton, P. Trends in Biochem. Sci. 24:34-35, 1999) for greater accuracy. Similarly transmembrane (TM) domains can be identified by multiple prediction methods. (Pasquier, et. al, Protein Eng. 12:381-385, 1999, Sonnhammer et al., In Proc. of Sixth Int. Conf. on Intelligent Systems for Molecular Biology, p. 175-182, Ed J. Glasgow, T. Littlejohn, F. Major, R. Lathrop, D. Sankoff, and C. Sensen Menlo Park, Calif.: AAAI Press, 1998, Klein, et. al, Biochim. Biophys. Acta, 815:468, 1985, Nakai and Kanehisa Genomics, 14: 897-911, 1992). In ambiguous cases, locations of functional domains in well characterized proteins are used as a guide to assign a cellular localization. 
         [0019]    Putative functions or functional domains of novel proteins can be inferred from homologous regions in the database identified by BLAST searches (Altschul et. al. Nucleic Acid Res. 25: 3389-3402, 1997) and/or from a conserved domain database such as Pfam (BaBEMan et. al, Nucleic Acids Res. 27:260-262 1999) BLOCKS (Henikoff, et. al, Nucl. Acids Res. 28:228-230, 2000) and SMART (Ponting, et. al, Nucleic Acid Res. 27,229-232, 1999). Extracellular domains include regions adjacent to a transmembrane domain in a single transmembrane domain protein (out-in or type I class). For multiple transmembrane domains proteins, the extracellular domain also includes those regions between two adjacent transmembrane domains (in-out and out-in). For type II transmembrane domain proteins, for which the N-terminal region is cytoplasmic, regions following the transmembrane domain is generally extracellular. Secreted proteins on the other hand do not have a transmembrane domain and hence the whole protein is considered as extracellular. 
         [0020]    Membrane associated proteins can be engineered to delete the transmembrane domains, thus leaving the extracellular portions which can bind to ligands. Such soluble forms of transmembrane receptor proteins can be used to compete with natural forms for binding to ligand. Thus such soluble forms act as inhibitors and can be used therapeutically as anti-angiogenic agents, as diagnostic tools for the quantification of natural ligands, and in assays for the identification of small molecules which modulate or mimic the activity of a BEM:ligand complex. 
         [0021]    Alternatively, the endothelial markers themselves can be used as vaccines to raise an immune response in the vaccinated animal or human. For such uses, a protein, or immunogenic fragment of such protein, corresponding to the intracellular, extracellular or secreted BEM of interest is administered to a subject. The immogenic agent may be provided as a purified preparation or in an appropriately expressing cell. The administration may be direct, by the delivery of the immunogenic agent to the subject, or indirect, through the delivery of a nucleic acid encoding the immunogenic agent under conditions resulting in the expression of the immunogenic agent of interest in the subject. The BEM of interest may be delivered in an expressing cell, such as a purified population of breast tumor endothelial cells or a population of fused breast tumor endothelial and dendritic cells. Nucleic acids encoding the BEM of interest may be delivered in a viral or non-viral delivery vector or vehicle. Non-human sequences encoding the human BEM of interest or other mammalian homolog can be used to induce the desired immunologic response in a human subject. For several of the BEMs of the present invention, mouse, rat or other ortholog sequences can be obtained from the literature or using techniques well within the skill of the art. 
         [0022]    Endothelial cells can be identified using the markers which are disclosed herein as being endothelial cell specific. Antibodies specific for such markers can be used to identify such cells, by contacting the antibodies with a population of cells containing some endothelial cells. The presence of cross-reactive material with the antibodies identifies particular cells as endothelial. Similarly, lysates of cells can be tested for the presence of cross-reactive material. Any known format or technique for detecting cross-reactive material can be used including, immunoblots, radioimmunoassay, ELISA, immunoprecipitation, and immunohistochemistry. In addition, nucleic acid probes for these markers can also be used to identify endothelial cells. Any hybridization technique known in the art including Northern blotting, RT-PCR, microarray hybridization, and in situ hybridization can be used. 
         [0023]    One can identify breast tumor endothelial cells for diagnostic purposes, testing cells suspected of containing one or more BEMs. One can test both tissues and bodily fluids of a subject. For example, one can test a patient&#39;s blood for evidence of intracellular and membrane associated BEMs, as well as for secreted BEMs. Of particular interest in this context is the testing of breast duct fluid. Intracellular and/or membrane associated BEMs may be present in bodily fluids as the result of high levels of expression of these factors and/or through lysis of cells expressing the BEMs. 
         [0024]    Populations of various types of endothelial cells can also be made using the antibodies to endothelial markers of the invention. The antibodies can be used to purify cell populations according to any technique known in the art, including but not limited to fluorescence activated cell sorting. Such techniques permit the isolation of populations which are at least 50, 60, 70, 80, 90, 92, 94, 95, 96, 97, 98, and even 99% the type of endothelial cell desired, whether normal, tumor, or pan-endothelial. Antibodies can be used to both positively select and negatively select such populations. Preferably at least 1, 5, 10, 15, 20, or 25 of the appropriate markers are expressed by the endothelial cell population. 
         [0025]    Populations of endothelial cells made as described herein, can be used for screening drugs to identify those suitable for inhibiting the growth of tumors by virtue of inhibiting the growth of the tumor vasculature. 
         [0026]    Populations of endothelial cells made as described herein, can be used for screening candidate drugs to identify those suitable for modulating angiogenesis, such as for inhibiting the growth of tumors by virtue of inhibiting the growth of endothelial cells, such as inhibiting the growth of the tumor or other undesired vasculature, or alternatively, to promote the growth of endothelial cells and thus stimulate the growth of new or additional large vessel or microvasculature. 
         [0027]    Inhibiting the growth of endothelial cells means either regression of vasculature which is already present, or the slowing or the absence of the development of new vascularization in a treated system as compared with a control system. By stimulating the growth of endothelial cells, one can influence development of new (neovascularization) or additional vasculature development (revascularization). A variety of model screening systems are available in which to test the angiogenic and/or anti-angiogenic properties of a given candidate drug. Typical tests involve assays measuring the endothelial cell response, such as proliferation, migration, differentiation and/or intracellular interaction with a given candidate drug. By such tests, one can study the signals and effects of the test stimuli. Some common screens involve measurement of the inhibition of heparanase, endothelial tube formation on Matrigel, scratch induced motility of endothelial cells, platelet-derived growth factor driven proliferation of vascular smooth muscle cells, and the rat aortic ring assay (which provides an advantage of capillary formation rather than just one cell type). 
         [0028]    Drugs can be screened for the ability to mimic or modulate, inhibit or stimulate, growth of tumor endothelium cells and/or normal endothelial cells. Drugs can be screened for the ability to inhibit tumor endothelium growth but not normal endothelium growth or survival. Similarly, human cell populations, such as normal endothelium populations or breast tumor endothelial cell populations, can be contacted with test substances and the expression of breast tumor endothelial markers and/or normal endothelial markers determined. Test substances that decrease the expression of breast tumor endothelial markers (BEMs) are candidates for inhibiting angiogenesis and the growth of tumors. In cases where the activity of a BEM is known, agents can be screened for their ability to decrease or increase the activity. 
         [0029]    For those breast tumor endothelial markers identified as containing transmembrane regions, it is desirable to identify drug candidates capable of binding to the BEM receptors found at the cell surface. For some applications, the identification of drug candidates capable of blocking the BEM receptor from its native ligand will be desired. For some applications, the identification of a drug candidate capable of binding to the BEM receptor may be used as a means to deliver a therapeutic or diagnostic agent. For other applications, the identification of drug candidates capable of mimicking the activity of the native ligand will be desired. Thus, by manipulating the binding of a transmembrane BEM receptor:ligand complex, one may be able to promote or inhibit further development of endothelial cells and hence, vascularization. 
         [0030]    For those breast tumor endothelial markers identified as being secreted proteins, i.e., extracellular, it is desirable to identify drug candidates capable of binding to the secreted BEM protein. For some applications, the identification of drug candidates capable of interfering with the binding of the secreted BEM it is native receptor. For other applications, the identification of drug candidates capable of mimicking the activity of the native receptor will be desired. Thus, by manipulating the binding of the secreted BEM:receptor complex, one may be able to promote or inhibit futher development of endothelial cells, and hence, vascularization. 
         [0031]    Expression can be monitored according to any convenient method. Protein or mRNA can be monitored. Any technique known in the art for monitoring specific genes&#39; expression can be used, including but not limited to ELISAs, SAGE, microarray hybridization, Western blots. Changes in expression of a single marker may be used as a criterion for significant effect as a potential pro-angiogenic, anti-angiogenic or anti-tumor agent. However, it also may be desirable to screen for test substances that are able to modulate the expression of at least 5, 10, 15, or 20 of the relevant markers, such as the tumor or normal endothelial markers Inhibition of BEM protein activity can also be used as a drug screen. 
         [0032]    Test substances for screening can come from any source. They can be libraries of natural products, combinatorial chemical libraries, biological products made by recombinant libraries, etc. The source of the test substances is not critical to the invention. The present invention provides means for screening compounds and compositions that may previously have been overlooked in other screening schemes. Nucleic acids and the corresponding encoded proteins of the markers of the present invention can be used therapeutically in a variety of modes. BEMs can be used to stimulate the growth of vasculature, such as for wound healing or to circumvent a blocked vessel. The nucleic acids and encoded proteins can be administered by any means known in the art. Such methods include, using liposomes, nanospheres, viral vectors, non-viral vectors comprising polycations, etc. Suitable viral vectors include adenovirus, retroviruses, and sindbis virus. Administration modes can be any known in the art, including parenteral, intravenous, intramuscular, intraperitoneal, topical, intranasal, intrarectal, intrabronchial, etc. 
         [0033]    Specific biological antagonists of BEMs can also be used to therapeutic benefit. For example, antibodies, T cells specific for a BEM, antisense to a BEM, interferance RNA to a BEM, and ribozymes specific for a BEM can be used to restrict, inhibit, reduce, and/or diminish tumor or other abnormal or undesirable vasculature growth. Such antagonists can be administered as is known in the art for these classes of antagonists generally. Anti-angiogenic drugs and agents can be used to inhibit tumor growth, as well as to treat diabetic retinopathy, rheumatoid arthritis, psoriasis, polycystic kidney disease (PKD), and other diseases requiring angiogenesis for their pathologies. 
         [0034]    Mouse counterparts to human BEMs can be used in mouse cancer models or in cell lines or in vitro to evaluate potential anti-angiogenic or anti-tumor compounds or therapies. Their expression can be monitored as an indication of effect. Mouse BEMs can be used as antigens for raising antibodies which can be tested in mouse tumor models. Mouse BEMs with transmembrane domains are particularly preferred for this purpose. Mouse BEMs can also be ued as vaccines to raise an immunological response in a human to the human ortholog. 
         [0035]    The above disclosure generally describes the present invention. All references disclosed herein are expressly incorporated by reference in their entireties. A more complete understanding can be obtained by reference to the following specific examples which are provided herein for purposes of illustration only, and are not intended to limit the scope of the invention. 
       Example 1 
       [0036]    Function of BEM proteins was determined using bioinformatics tools. BEMs that are putative functional receptors with short cytoplasmic tails make particularly interesting targets. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 Breast Tumor Endothelial Putative Functional 
               
               
                 Receptors with Short Cytoplasmic Tails 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.181418 
                 KIAA0152 gene product 
                 — 
                 055545 
               
               
                 Hs.25691 
                 receptor (calcitonin) activity 
                 605155 
                 005847 
               
               
                   
                 modifying protein 3 
               
               
                 Hs.9598 
                 sema domain 
                 — 
                 BAB212835 
               
               
                   
               
             
          
         
       
     
       Example 2 
       [0037]    Protein kinases were identified among the BEMs. These are particularly good druggable targets, especially for small molecules. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 Protein Kinases 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.100009 
                 cyclin-dependent 
                 123828 
                   
               
               
                   
                 kinase 3 
               
               
                 Hs.143897 
                 dysferlin, limb girdle 
                 603009 
                 NP_003485 
               
               
                   
                 muscular dystrophy 2B 
               
               
                   
                 (autosomal recessive) 
               
               
                 Hs.184367 
                 Ca2+-promoted Ras 
                   
                 BAA25464 
               
               
                   
                 inactivator 
               
               
                 Hs.246857 
                 mitogen-activated 
                 602896 
                 NP_620708 
               
               
                   
                 protein kinase 9 
               
               
                 Hs.75087 
                 FAST kinase 
                 606965 
                 NP-079372 
               
               
                 Hs.296323 
                 serum/glucocorticoid 
                 602958 
                 NP_005618 
               
               
                   
                 regulated kinase 
               
               
                 Hs.246857 
                 mitogen-activated 
                 602986 
                 NP_620708 
               
               
                   
                 protein kinase 
               
               
                   
               
             
          
         
       
     
       Example 3 
       [0038]    Kinases with non-protein substrates were also identified. These similarly are believed to be exceedingly good druggable targets. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 Kinases with non-protein substrates 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.118625 
                 hexokinase 1 
                 142600 
                 NP_277035 
               
               
                 Hs.82689 
                 tumor rejection antigen (gp96) 
                 191175 
                 NP_003290 
               
               
                   
                 1 
               
               
                   
               
             
          
         
       
     
       Example 4 
       [0039]    Growth factors were identified among the BEMs: 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 Growth factors 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.91143 
                 jagged 1 (Alagille syndrome) 
                 601920 
                 NP_000205 
               
               
                 Hs.119206 
                 insulin-like growth factor 
                 602867 
                 NP_001544 
               
               
                   
                 binding protein 7 
               
               
                 Hs.1516 
                 insulin-like growth factor 
                 146733 
                 NP_001543 
               
               
                   
                 binding protein 4 
               
               
                 Hs.211573 
                 heparan sulfate proteoglycan 2 
                 142461 
                 NP_005520 
               
               
                   
                 (perlecan) 
               
               
                 Hs.75111 
                 protease, serine, 11 (IGF 
                 602194 
                 NP_002766 
               
               
                   
                 binding) 
               
               
                 Hs.8546 
                 Notch homolog 3 ( Drosophila ) 
                 600276 
                 NP_000426 
               
               
                   
               
             
          
         
       
     
       Example 5 
       [0040]    Phosphatases, like kinases, are readily amenable to screening for inhibitors, especially small molecule inhibitors: 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 Phosphatases 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.8997 
                 heat shock 70 kDa protein 
                 140550 
                 NP_005336 
               
               
                   
                 1A/1B [ Homo sapiens   
               
               
                 Hs.205353 
                 ectonucleoside triphosphate 
                 601752 
                 NP_001767 
               
               
                   
                 diphosphohydrolase 1 isoform 
               
               
                   
                 1 [ Homo sapiens ] 
               
               
                 Hs.43666 
                 protein tyrosine phosphatase 
                 606449 
                 NP_116000 
               
               
                   
                 type IVA 3 isoform 1 
               
               
                   
                 [ Homo sapiens ] 
               
               
                 Hs.6147 
                 tensin-like C1 domain- 
                 — 
                 NP_056134 
               
               
                   
                 containing phosphatase 
               
               
                   
                 isoform 1 [ Homo sapiens ] 
               
               
                   
               
             
          
         
       
     
       Example 6 
       [0041]    GPCRs were identified among the BEMs: 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 GPCRs 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.17170 
                 G protein-coupled receptor 4 
                 600551 
                 NP_005273 
               
               
                   
               
             
          
         
       
     
       Example 7 
       [0042]    The cellular location of the BEMs was determined to be either cytoplasmic, extracellular, membrane, or nuclear, as shown below. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 Extracellular Proteins 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.75415 
                 Beta-2-microglobulin 
                 109700 
                 NP_004039 
               
               
                 Hs.821 
                 Biglycan 
                 301870 
                 NP_001702 
               
               
                 Hs.172928 
                 collagen, type I, alpha 1 
                 120150 
                 NP_000079 
               
               
                 Hs.119571 
                 collagen, type III, alpha 1 
                 120180 
                 NP_000081 
               
               
                   
                 (Ehlers-Danlos syndrome 
               
               
                   
                 type IV, autosomal dominant) 
               
               
                 Hs.119129 
                 collagen, type IV, alpha 1 
                 120130 
                 NP_001836 
               
               
                 Hs.75617 
                 collagen, type IV, alpha 2 
                 120090 
                 NP_001837 
               
               
                 Hs.235368 
                 collagen, type V, alpha 3 
                 120216 
                 NP_056534 
               
               
                 Hs.159263 
                 collagen, type VI, alpha 2 
                 120240 
                 NP_001840 
               
               
                 Hs.78409 
                 collagen, type XVIII, alpha 1 
                 120328 
                 NP_085059 
               
               
                 Hs.278625 
                 complement component 4B 
                 120820 
                 NP_000583 
               
               
                 Hs.230 
                 Fibromodulin 
                 600245 
                 NP_002014 
               
               
                 Hs.211573 
                 heparan sulfate proteoglycan 2 
                 142461 
                 NP_005520 
               
               
                   
                 (perlecan) 
               
               
                 Hs.1516 
                 insulin-like growth factor 
                 146733 
                 NP_001543 
               
               
                   
                 binding protein 4 
               
               
                 Hs.119206 
                 insulin-like growth factor 
                 602867 
                 NP_001544 
               
               
                   
                 binding protein 7 
               
               
                 Hs.49215 
                 integrin-binding sialoprotein 
                 147563 
                 NP_004958 
               
               
                   
                 (bone sialoprotein, bone 
               
               
                   
                 sialoprotein II) 
               
               
                 Hs.79339 
                 lectin, galactoside-binding, 
                 600626 
                 NP_005558 
               
               
                   
                 soluble, 3 binding protein 
               
               
                 Hs.106747 
                 likely homolog of rat and 
                   
                 NP_067639 
               
               
                   
                 mouse retinoid-inducible 
               
               
                   
                 serine carboxypeptidase 
               
               
                 Hs.365706 
                 matrix Gla protein 
                 154870 
                 NP_000891 
               
               
                 Hs.151738 
                 matrix metalloproteinase 9 
                 120361 
                 NP_004985 
               
               
                   
                 (gelatinase B, 92 kDa 
               
               
                   
                 gelatinase, 92 kDa type IV 
               
               
                   
                 collagenase) 
               
               
                 Hs.699 
                 peptidylprolyl isomerase B 
                 123841 
                 NP_000933 
               
               
                   
                 (cyclophilin B) 
               
               
                 Hs.75111 
                 protease, serine, 11 (IGF 
                 602194 
                 NP_002766 
               
               
                   
                 binding) 
               
               
                 Hs.25338 
                 protease, serine, 23 
               
               
                 Hs.78224 
                 ribonuclease, RNase A family, 
                 180440 
                 AAH05324 
               
               
                   
                 1 (pancreatic) 
               
               
                 Hs.111779 
                 secreted protein, acidic, 
                 182120 
                 NP_003109 
               
               
                   
                 cysteine-rich (osteonectin) 
               
               
                 Hs.82085 
                 serine (or cysteine) 
                 173360 
                 NP_000593 
               
               
                   
                 proteinase inhibitor, clade E 
               
               
                   
                 (nexin, plasminogen activator 
               
               
                   
                 inhibitor type 1), member 1 
               
               
                 Hs.179573 
                 TEM10, COL1A2 involved in 
                 120160 
                 NP_000080 
               
               
                   
                 tissue remodeling 
               
               
                 Hs.356624 
                 TEM11, nidogen (enactin) 
                 131390 
                 NP_002499 
               
               
                 Hs.5831 
                 tissue inhibitor of 
                 305370 
                 NP_003245 
               
               
                   
                 metalloproteinase 1 (erythroid 
               
               
                   
                 potentiating activity, 
               
               
                   
                 collagenase inhibitor) 
               
               
                 Hs.82689 
                 tumor rejection antigen (gp96) 1 
                 191175 
                 NP_003290 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                 Membrane Proteins 
               
             
          
           
               
                   
                   
                   
                 TM 
                   
                 Orientation 
               
               
                 Unigene ID 
                 Function 
                 Protein 
                 Domains 
                 TM Location 
                 of N-terminus 
               
               
                   
               
             
          
           
               
                 Hs.202 
                 benzodiazapine receptor (peripheral) 
                 NP_000705 
                 3 
                 107-129, 78-100, 
                 OUT 
               
               
                   
                   
                   
                   
                 133-155 
               
               
                 Hs.76206 
                 cadherin 5, type 2, VE-cadherin (vascular epithelium) 
                 NP_001786 
                 1 
                 598-620 
                 Unsure 
               
               
                 Hs.122359 
                 calcium channel, voltage-dependent, alpha 1H subunit 
                 NP_066921 
                 19 
                 1370-1392, 1614-1636, 
                 IN 
               
               
                   
                   
                   
                   
                 1533-1555, 141-163, 
               
               
                   
                   
                   
                   
                 915-937, 396-418, 
               
               
                   
                   
                   
                   
                 1651-1673, 1745-1767, 
               
               
                   
                   
                   
                   
                 990-1012, 234-256, 
               
               
                   
                   
                   
                   
                 1430-1452, 1333-1355, 
               
               
                   
                   
                   
                   
                 1680-1702, 855-877, 
               
               
                   
                   
                   
                   
                 1295-1316, 826-848, 
               
               
                   
                   
                   
                   
                 100-122, 1840-1862, 
               
               
                   
                   
                   
                   
                 364-386 
               
               
                 Hs.84298 
                 CD74 antigen (invariant polypeptide of major 
                 NP_004346 
                 1 
                 49-71 
                 IN 
               
               
                   
                 histocompatibility complex, class II antigen-associated) 
               
               
                 Hs.1244 
                 CD9 antigen (p24) 
                 NP_001760 
                 4 
                 59-81, 88-110, 
                 IN 
               
               
                   
                   
                   
                   
                 12-34, 194-216 
               
               
                 Hs.143897 
                 dysferlin, limb girdle muscular dystrophy 2B 
                 NP_003485 
                 1 
                 2045-2067 
                 Unsure 
               
               
                   
                 (autosomal recessive) 
               
               
                 Hs.205353 
                 ectonucleoside triphosphate diphosphohydrolase 1 
                 NP_001767 
                 1 
                 477-499 
                 IN 
               
               
                 Hs.17170 
                 G protein-coupled receptor 4 
                 NP_005273 
                 5 
                 55-77, 92-113, 
                 OUT 
               
               
                   
                   
                   
                   
                 20-42, 225-244, 
               
               
                   
                   
                   
                   
                 183-205 
               
               
                 Hs.25549 
                 hypothetical protein FLJ20898 
                 NP_078876 
                 3 
                 102-124, 139-161, 
                 Unsure 
               
               
                   
                   
                   
                   
                 168-190 
               
               
                 Hs.277704 
                 hypoxia up-regulated 1 
                 NP_006380 
                 1 
                 13-35 
                 IN 
               
               
                 Hs.76095 
                 Immediate early response 3 
                 NP_434702 
                 1 
                 123-145 
                 Unsure 
               
               
                 Hs.265827 
                 interferon, alpha-inducible protein (clone IFI-6-16) 
                 NP_075011 
                 2 
                 5-24, 44-66 
                 IN 
               
               
                 Hs.91143 
                 jagged 1 (Alagille syndrome) 
                 NP_000205 
                 1 
                 1069-1091 
                 Unsure 
               
               
                 Hs.181418 
                 KIAA0152 gene product 
                 NP_055545 
                 1 
                 271-290 
                 OUT 
               
               
                 Hs.79356 
                 Lysosomal-associated multispanning membrane 
                 NP_006753 
                 5 
                 63-85, 100-121, 
                 Unsure 
               
               
                   
                 protein-5 
                   
                   
                 142-164, 15-37, 
               
               
                   
                   
                   
                   
                 184-206 
               
               
                 Hs.77961 
                 major histocompatibility complex, class I, B 
                 NP_005505 
                 1 
                 308-330 
                 OUT 
               
               
                 Hs.277477 
                 major histocompatibility complex, class I, C 
                 NP_002108 
                 1 
                 308-330 
                 OUT 
               
               
                 Hs.110024 
                 NADH: ubiquinone oxidoreductase MLRQ subunit 
                 NP_064527 
                 1 
                 20-42 
                 Unsure 
               
               
                   
                 homolog 
               
               
                 Hs.8546 
                 Notch homolog 3 ( Drosophila ) 
                 NP_000426 
                 3 
                 1641-1663, 1496-1518, 
                 Unsure 
               
               
                   
                   
                   
                   
                 20-42 
               
               
                 Hs.107125 
                 plasmalemma vesicle associated protein 
                 NP_112600 
                 1 
                 42-64 
                 IN 
               
               
                 Hs.83974 
                 solute carrier family 21 (prostaglandin transporter), 
                 NP_005621 
                 12 
                 256-278, 363-385, 
                 Unsure 
               
               
                   
                 member 2 
                   
                   
                 397-419, 100-122, 
               
               
                   
                   
                   
                   
                 208-230, 326-348, 
               
               
                   
                   
                   
                   
                 173-195, 514-536, 
               
               
                   
                   
                   
                   
                 71-93, 557-576, 
               
               
                   
                   
                   
                   
                 606-628, 25-47 
               
               
                 Hs.125359 
                 TEM13, Thy-1 cell surface antigen 
                 NP_006279 
                 1 
                 140-161 
                 Unsure 
               
               
                 Hs.125036 
                 TEM17 
                 NP_065138 
                 1 
                 425-447 
                 OUT 
               
               
                 Hs.9598 
                 sema domain, immunoglobulin domain (Ig) 
                 BAB21836 
                 1 
                 727-794 
                 OUT 
               
               
                 Hs.202 
                 Benzodiazapine receptor (peripheral)-mitochondrial 
                 NP_00715 
                 3 
                 107-129, 78-100, 
                 OUT 
               
               
                   
                   
                   
                   
                 133-155 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 Nuclear Proteins 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.244 
                 amino-terminal enhancer of 
                 600188 
                   
               
               
                   
                 split 
               
               
                 Hs.154029 
                 bHLH factor Hes4 
                   
                 NP_066993 
               
               
                 Hs.75450 
                 delta sleep inducing peptide, 
                 602960 
               
               
                   
                 immunoreactor 
               
               
                 Hs.75087 
                 FAST kinase 
                 606965 
                 NP_079372 
               
               
                 Hs.356668 
                 guanine nucleotide binding 
                 600874 
                 NP_005265 
               
               
                   
                 protein (G protein), gamma 5 
               
               
                 Hs.406410 
                 H19, imprinted maternally 
                 103280 
                 BAB71280 
               
               
                   
                 expressed untranslated mRNA 
               
               
                 Hs.234434 
                 hairy/enhancer-of-split 
                 602953 
                 NP_036390 
               
               
                   
                 related with YRPW motif 1 
               
               
                 Hs.23823 
                 hairy/enhancer-of-split 
                   
                 NP_055386 
               
               
                   
                 related with YRPW motif-like 
               
               
                 Hs.15265 
                 heterogeneous nuclear 
                 607201 
                 NP_005817 
               
               
                   
                 ribonucleoprotein R 
               
               
                 Hs.8728 
                 hypothetical protein 
                   
                 CAB61365 
               
               
                   
                 DKFZp434G171 
               
               
                 Hs.240170 
                 hypothetical protein MGC2731 
                   
                 NP_076973 
               
               
                 Hs.146360 
                 hypothetical protein MGC34648 
                   
                 NP_689873 
               
               
                 Hs.337986 
                 hypothetical protein MGC4677 
                   
                 NP_443103 
               
               
                 Hs.197540 
                 hypoxia-inducible factor 1, 
                 603348 
                 NP_001521 
               
               
                   
                 alpha subunit (basic helix- 
               
               
                   
                 loop-helix transcription 
               
               
                   
                 factor) 
               
               
                 Hs.75061 
                 MARCKS-like protein 
                 602940 
                 NP_075385 
               
               
                 Hs.246857 
                 mitogen-activated protein 
                 602896 
                 NP_620708 
               
               
                   
                 kinase 9 
               
               
                 Hs.79110 
                 Nucleolin 
                 164035 
                 NP_005372 
               
               
                 Hs.298229 
                 prefoldin 2 
                   
                 NP_036526 
               
               
                 Hs.250655 
                 prothymosin, alpha (gene 
                 188390 
                 NP_002814 
               
               
                   
                 sequence 28) 
               
               
                 Hs.24950 
                 regulator of G-protein 
                 603276 
                 NP_003608 
               
               
                   
                 signaling 5 
               
               
                 Hs.76640 
                 RGC32 protein 
               
               
                 Hs.3109 
                 Rho GTPase activating protein 4 
                 300023 
                 NP_001657 
               
               
                 Hs.337445 
                 ribosomal protein L37 
                 604181 
                 NP_000988 
               
               
                 Hs.197114 
                 serine/arginine repetitive 
                 606032 
                 NP_057417 
               
               
                   
                 matrix 2 
               
               
                 Hs.48029 
                 snail homolog 1 ( Drosophila ) 
                 604238 
                 NP_005976 
               
               
                 Hs.168357 
                 T-box 2 
                 600747 
                 NP_005985 
               
               
                 Hs.332173 
                 transducin-like enhancer of 
                 601041 
                 NP_003251 
               
               
                   
                 split 2 (E(sp1) homolog, 
               
               
                   
                   Drosophila ) 
               
               
                 Hs.78465 
                 v-jun sarcoma virus 17 
                 165160 
                 NP_002219 
               
               
                   
                 oncogene homolog (avian) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 Cytoplasmic proteins 
               
             
          
           
               
                 Unigene ID 
                 Function 
                 OMIMID 
                 Protein 
               
               
                   
               
               
                 Hs.184367 
                 Ca2+-promoted Ras 
                   
                 BAA25464 
               
               
                   
                 inactivator 
               
               
                 Hs.2575 
                 calpain 1, (mu/l) large 
                 114220 
                 NP_005177 
               
               
                   
                 subunit 
               
               
                 Hs.100009 
                 cyclin-dependent kinase 3 
                 123828 
               
               
                 Hs.31053 
                 cytoskeleton-associated 
                 601303 
                 NP_001272 
               
               
                   
                 protein 1 
               
               
                 Hs.82646 
                 DnaJ (Hsp40) homolog, 
                 604572 
                 NP_006136 
               
               
                   
                 subfamily B, member 1 
               
               
                 Hs.169476 
                 glyceraldehyde-3- 
                 138400 
                 NP_002037 
               
               
                   
                 phosphate dehydrogenase 
               
               
                 Hs.77890 
                 guanylate cyclase 1, soluble, 
                 139397 
                 NP_000848 
               
               
                   
                 beta 3 
               
               
                 Hs.36927 
                 heat shock 105 Kd 
                   
                 NP_006635 
               
               
                 Hs.1197 
                 heat shock 10 kDa protein 1 
                 600141 
                 NP_002148 
               
               
                   
                 (chaperonin 10) 
               
               
                 Hs.8997 
                 heat shock 70 kDa protein 1A 
                 140550 
                 NP_005336 
               
               
                 Hs.180414 
                 heat shock 70 kDa protein 8 
                 600816 
                 NP_006588 
               
               
                 Hs.118625 
                 hexokinase 1 
                 142600 
                 NP_277035 
               
               
                 Hs.327412 
                   Homo sapiens  clone FLC1492 
               
               
                   
                 PRO3121 mRNA, complete cds 
               
               
                 Hs.833 
                 interferon, alpha-inducible 
                 147571 
                 NP_005092 
               
               
                   
                 protein (clone IFI-15K) 
               
               
                 Hs.150580 
                 putative translation 
                   
                 NP_005792 
               
               
                   
                 initiation factor 
               
               
                 Hs.173737 
                 ras-related C3 botulinum toxin 
                 602048 
               
               
                   
                 substrate 1 (rho family, small 
               
               
                   
                 GTP binding protein Rac1) 
               
               
                 Hs.119122 
                 ribosomal protein L13a 
               
               
                 Hs.111611 
                 ribosomal protein L27 
                 607526 
                 NP_000979 
               
               
                 Hs.177592 
                 ribosomal protein, large, P1 
                 180520 
               
               
                 Hs.12956 
                 Tax interaction protein 1 
                   
                 NP_055419 
               
               
                 Hs.251653 
                 tubulin, beta, 2 
                 602660 
                 NP_006079 
               
               
                   
               
             
          
         
       
     
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