bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of Host- and Tumor-Derived Proteinases Using a Custom Dual Species Microarray Reveals a Protective Role for Stromal Matrix Metalloproteinase-12 in Non–Small Cell Lung Cancer
Authors: Acuff Heath B. , Sinnamon Mark , Fingleton Barbara , Boone Braden , Levy Shawn E. , Chen Xiwu , Pozzi Ambra , Carbone David P. , Schwartz Donald R. , Moin Kamiar , Sloane Bonnie F. , Matrisian Lynn M. 
Published: August 2006

AbstractWe used a customized Affymetrix protease microarray (Hu/Mu ProtIn chip) designed to distinguish human and mouse genes to analyze the expression of proteases and protease inhibitors in lung cancer. Using an orthotopic lung cancer model, we showed that murine matrix metalloproteinase (MMP)-12, MMP-13, and cathepsin K were up-regulated in tumor tissue compared with normal mouse lung. To determine the relevance of stromal proteases detected using this model system, we compared the results to an analysis of human lung adenocarcinoma specimens using the U133 Plus 2.0 Affymetrix microarray. MMP-12, MMP-13, and cathepsin K showed an increase in expression in human tumors compared with normal lung similar to that seen in the orthotopic model. Immunohistochemical analysis confirmed MMP-12 expression in the stroma of human lung tumor samples. To determine the biological relevance of stromal MMP-12, murine Lewis lung carcinoma cells were injected into the tail vein of syngeneic wild-type (WT) and MMP-12-null mice. MMP-12-null and WT mice developed equivalent numbers of lung tumors; however, there was a 2-fold increase in the number of tumors that reached &gt;2 mm in diameter in MMP-12-null mice compared with WT controls. The increase in tumor size correlated with an increase in CD31-positive blood vessels and a decrease in circulating levels of the K1-K4 species of angiostatin. These results show a protective role for stromal MMP-12 in lung tumor growth. The use of the Hu/Mu ProtIn chip allows us to distinguish tumor- and host-derived proteases and guides the further analysis of the significance of these genes in tumor progression. (Cancer Res 2006; 66(16): 7968-75)
HuR Contributes to Cyclin E1 Deregulation in MCF-7 Breast Cancer Cells
Authors: Guo Xun , Hartley Rebecca S. 
Published: August 2006

Abstract
Many cancers overexpress cyclin E1 and its tumor-specific low molecular weight (LMW) isoforms. However, the mechanism of cyclin E1 deregulation in cancers is still not well understood. We show here that the mRNA-binding protein HuR increases cyclin E1 mRNA stability in MCF-7 breast carcinoma cells. Thus, mRNA stabilization may be a key event in the deregulation of cyclin E1 in MCF-7 cells. Compared with MCF10A immortalized breast epithelial cells, MCF-7 cells overexpress full-length cyclin E1 and its LMW isoforms and exhibit increased cyclin E1 mRNA stability. Increased mRNA stability is associated with a stable adenylation state and an increased ratio of cytoplasmic versus nuclear HuR. UV cross-link competition and UV cross-link immunoprecipitation assays verified that HuR specifically bound to the cyclin E1 3′-untranslated region. Knockdown of HuR with small interfering RNA (siRNA) in MCF-7 cells decreased cyclin E1 mRNA half-life (t1/2) and its protein level: a 22% decrease for the full-length isoforms and 80% decrease for the LMW isoforms. HuR siRNA also delayed G1-S phase transition and inhibited MCF-7 cell proliferation, which was partially recovered by overexpression of a LMW isoform of cyclin E1. Overexpression of HuR in MCF10A cells increased cyclin E1 mRNA t1/2 and its protein level. Taken together, our data show that HuR critically contributes to cyclin E1 overexpression and its growth-promoting function, at least in part by increasing cyclin E1 mRNA stability, which provides a new mechanism of cyclin E1 deregulation in breast cancer. (Cancer Res 2006; 66(16): 7948-56)
Hypoxia Enhances Lysophosphatidic Acid Responsiveness in Ovarian Cancer Cells and Lysophosphatidic Acid Induces Ovarian Tumor Metastasis In vivo
Authors: Kim Kwan-Sik , Sengupta Saubhik , Berk Michael , Kwak Yong-Geun , Escobar Pedro F. , Belinson Jerome , Mok Samuel C. , Xu Yan 
Published: August 2006

Abstract
Lysophosphatidic acid (LPA) is elevated in ascites of ovarian cancer patients and stimulates growth and other activities of ovarian cancer cells in vitro. Tissue hypoxia is a critical factor for tumor aggressiveness and metastasis in cancers. We tested whether the ascites of ovarian cancer is hypoxic and whether hypoxia influences the effects of LPA on ovarian cancer cells. We found that ovarian ascitic fluids were hypoxic in vivo. Enhanced cellular responsiveness to LPA, including migration and/or invasion of ovarian cancer cells, was observed under hypoxic conditions. This enhancement could be completely blocked by geldanamycin or a small interfering RNA targeting hypoxia-inducible factor 1α (HIF1α). LPA-induced cell migration required cytosolic phospholipase A2 (cPLA2) and LPA stimulates cPLA2 phosphorylation in a HIF1α-dependent manner under hypoxia conditions. Furthermore, we show for the first time that exogenous LPA enhances tumor metastasis in an orthotopic ovarian cancer model and HIFα expression in tumors. 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (an inhibitor of the heat shock protein 90) effectively blocked LPA-induced tumor metastasis in vivo. Together, our data indicate that hypoxic conditions are likely to be pathologically important for ovarian cancer development. HIF1α plays a critical role in enhancing and/or sensitizing the role of LPA on cell migration and invasion under hypoxic conditions, where cPLA2 is required for LPA-induced cell migration. (Cancer Res 2006; 66(16): 7983-90)
Coregulation of Estrogen Receptor by ERBB4/HER4 Establishes a Growth-Promoting Autocrine Signal in Breast Tumor Cells
Authors: Zhu Yun , Sullivan Lacey L. , Nair Sujit S. , Williams Christopher C. , Pandey Arvind K. , Marrero Luis , Vadlamudi Ratna K. , Jones Frank E. 
Published: August 2006

Abstract
Although crosstalk between cell-surface and nuclear receptor signaling pathways has been implicated in the development and progression of endocrine-regulated cancers, evidence of direct coupling of these signaling pathways has remained elusive. Here we show that estrogen promotes an association between extranuclear estrogen receptor α (ER) and the epidermal growth factor receptor (EGFR) family member ERBB4. Ectopically expressed as well as endogenous ERBB4 interacts with and potentiates ER transactivation, indicating that the ERBB4/ER interaction is functional. Estrogen induces nuclear translocation of the proteolytic processed ERBB4 intracellular domain (4ICD) and nuclear translocation of 4ICD requires functional ligand-bound ER. The nuclear ER/4ICD complex is selectively recruited to estrogen-inducible gene promoters such as progesterone receptor (PgR) and stromal cell–derived factor 1 (SDF-1) but not to trefoil factor 1 precursor (pS2). Consistent with 4ICD-selective promoter binding, suppression of ERBB4 expression by interfering RNA shows that 4ICD coactivates ER transcription at the PgR and SDF-1 but not the pS2 promoter. Significantly, ERBB4 itself is an estrogen-inducible gene and the ERBB4 promoter harbors a consensus estrogen response element (ERE) half-site with overlapping activator protein-1 elements that bind ER and 4ICD in response to estrogen. Using a cell proliferation assay and a small interfering RNA approach, we show that ERBB4 expression is required for the growth-promoting action of estrogen in the T47D breast cancer cell line. Our results indicate that ERBB4 is a unique coregulator of ER, directly coupling extranuclear and nuclear estrogen actions in breast cancer. We propose that the contribution of an autocrine ERBB4/ER signaling pathway to tumor growth and therapeutic response should be considered when managing patients with ER-positive breast cancer. (Cancer Res 2006; 66(16): 7991-8)
Genome-Wide Expression Profiling Reveals EBV-Associated Inhibition of MHC Class I Expression in Nasopharyngeal Carcinoma
Authors: Sengupta Srikumar , den Boon Johan A. , Chen I-How , Newton Michael A. , Dahl David B. , Chen Meng , Cheng Yu-Juen , Westra William H. , Chen Chien-Jen , Hildesheim Allan , Sugden Bill , Ahlquist Paul 
Published: August 2006

Abstract
To identify the molecular mechanisms by which EBV-associated epithelial cancers are maintained, we measured the expression of essentially all human genes and all latent EBV genes in a collection of 31 laser-captured, microdissected nasopharyngeal carcinoma (NPC) tissue samples and 10 normal nasopharyngeal tissues. Global gene expression profiles clearly distinguished tumors from normal healthy epithelium. Expression levels of six viral genes (EBNA1, EBNA2, EBNA3A, EBNA3B, LMP1, and LMP2A) were correlated among themselves and strongly inversely correlated with the expression of a large subset of host genes. Among the human genes whose inhibition was most strongly correlated with increased EBV gene expression were multiple MHC class I HLA genes involved in regulating immune response via antigen presentation. The association between EBV gene expression and inhibition of MHC class I HLA expression implies that antigen display is either directly inhibited by EBV, facilitating immune evasion by tumor cells, and/or that tumor cells with inhibited presentation are selected for their ability to sustain higher levels of EBV to take maximum advantage of EBV oncogene-mediated tumor-promoting actions. Our data clearly reflect such tumor promotion, showing that deregulation of key proteins involved in apoptosis (BCL2-related protein A1 and Fas apoptotic inhibitory molecule), cell cycle checkpoints (AKIP, SCYL1, and NIN), and metastasis (matrix metalloproteinase 1) is closely correlated with the levels of EBV gene expression in NPC. (Cancer Res 2006; 66(16): 7999-8006)
Role of Focal Adhesion Kinase and Phosphatidylinositol 3′-Kinase in Integrin Fibronectin Receptor-Mediated, Matrix Metalloproteinase-1–Dependent Invasion by Metastatic Prostate Cancer Cells
Authors: Zeng Zhao-Zhu , Jia Yifeng , Hahn Nathan J. , Markwart Sonja M. , Rockwood Korrene F. , Livant Donna L. 
Published: August 2006

Abstract
α5β1 Integrin interacts with the PHSRN sequence of plasma fibronectin, causing constitutive invasion by human prostate cancer cells. Inhibition of this process reduces tumorigenesis and prevents metastasis and recurrence. In this study, naturally serum-free basement membranes were used as in vitro invasion substrates. Immunoassays were employed to dissect the roles of focal adhesion kinase (FAK), phosphatidylinositol 3′-kinase (PI3K), and protein kinase Cδ (PKCδ) in α5β1-mediated, matrix metalloproteinase-1 (MMP-1)–dependent invasion by metastatic human DU 145 prostate cancer cells. We found that a peptide composed of the PHSRN sequence induced rapid FAK phosphorylation at Tyr397 (Y397), a site whose phosphorylation is associated with kinase activation. The technique of RNA silencing [small interfering RNA (siRNA)] confirmed the role of FAK in PHSRN-induced invasion. PHSRN also induced the association of the p85-regulatory subunit of PI3K with FAK at a time corresponding to FAK phosphorylation and activation, and maximal PI3K activity occurred at this same time. The necessity of PI3K activity in both PHSRN-induced invasion and MMP-1 expression was confirmed by using specific PI3K inhibitors. By employing a specific inhibitor, Rottlerin, and by using siRNA, we also found that PKCδ, a PI3K substrate found in focal adhesions, functions in PHSRN-induced invasion. In addition, the induction of MMP-1 in PHSRN-treated DU 145 cells was shown by immunoblotting, and the role of MMP-1 in PHSRN-induced invasion was confirmed by the use of blocking anti-MMP-1 monoclonal antibody. Finally, a close temporal correspondence was observed between PHSRN-induced invasion and PHSRN-induced MMP-1 activity in DU 145 cells. (Cancer Res 2006; 66(16): 8091-9)
Cortactin Overexpression Regulates Actin-Related Protein 2/3 Complex Activity, Motility, and Invasion in Carcinomas with Chromosome 11q13 Amplification
Authors: Rothschild Brian L. , Shim Ann H. , Ammer Amanda Gatesman , Kelley Laura C. , Irby Kimberly B. , Head Julie A. , Chen Lin , Varella-Garcia Marileila , Sacks Peter G. , Frederick Barbara , Raben David , Weed Scott A. 
Published: August 2006

AbstractCarcinoma cell motility and invasion are prerequisites for tumor cell metastasis, which requires regulation of the actin cytoskeleton. Cortactin is an actin-related protein 2/3 (Arp2/3) complex–activating and filamentous (F)-actin–binding protein that is implicated in tumor cell motility and metastasis, partially by its ability to become tyrosine phosphorylated. Cortactin is encoded by the CTTN gene and maps to chromosome 11q13, a region amplified in many carcinomas, including head and neck squamous cell carcinoma (HNSCC). CTTN gene amplification is associated with lymph node metastasis and poor patient outcome, and cortactin overexpression enhances motility in tumor cells lacking 11q13 amplification. However, a direct link between increased motility and invasion has not been reported in tumor cells with chromosome 11q13 amplification and cortactin overexpression. In this study, we have examined the relationship between CTTN amplification and tumor cell motility in HNSCC. In 11 of 39 (28%) HNSCC cases, cortactin overexpression determined by immunohistochemistry correlates with lymph node metastasis and CTTN gene amplification. HNSCC cells containing cortactin gene amplification and protein overexpression display increased binding and activation of Arp2/3 complex, and were more motile and invasive than HNSCC cells lacking CTTN amplification. Down-regulation of cortactin expression in CTTN-amplified HNSCC cells by small interfering RNA impairs HNSCC motility and invasion. Treatment of HNSCC cells with the epidermal growth factor receptor inhibitor gefitinib inhibits HNSCC motility and down-regulates cortactin tyrosine phosphorylation. These data suggest that cortactin may be a valid prognostic and therapeutic marker for invasive and metastatic HNSCC and other carcinomas with 11q13 amplification. (Cancer Res 2006; 66(16): 8017-25)
Deficiency in the Repair of DNA Damage by Homologous Recombination and Sensitivity to Poly(ADP-Ribose) Polymerase Inhibition
Authors: McCabe Nuala , Turner Nicholas C. , Lord Christopher J. , Kluzek Katarzyna , Białkowska Aneta , Swift Sally , Giavara Sabrina , O'Connor Mark J. , Tutt Andrew N. , Zdzienicka Małgorzata Z. , Smith Graeme C.M. , Ashworth Alan 
Published: August 2006

Abstract
Deficiency in either of the breast cancer susceptibility proteins BRCA1 or BRCA2 induces profound cellular sensitivity to the inhibition of poly(ADP-ribose) polymerase (PARP) activity. We hypothesized that the critical role of BRCA1 and BRCA2 in the repair of double-strand breaks by homologous recombination (HR) was the underlying reason for this sensitivity. Here, we examine the effects of deficiency of several proteins involved in HR on sensitivity to PARP inhibition. We show that deficiency of RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity. This suggests that BRCA-deficient cells are, at least in part, sensitive to PARP inhibition because of HR deficiency. These results indicate that PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutation-associated tumors but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway or displaying properties of ‘BRCAness.’ (Cancer Res 2006; 66(16): 8109-15)
Cross-Talk between Nucleotide Excision and Homologous Recombination DNA Repair Pathways in the Mechanism of Action of Antitumor Trabectedin
Authors: Herrero Ana B. , Martín-Castellanos Cristina , Marco Esther , Gago Federico , Moreno Sergio 
Published: August 2006

Abstract
Trabectedin (Yondelis) is a potent antitumor drug that has the unique characteristic of killing cells by poisoning the DNA nucleotide excision repair (NER) machinery. The basis for the NER-dependent toxicity has not yet been elucidated but it has been proposed as the major determinant for the drug's cytotoxicity. To study the in vivo mode of action of trabectedin and to explore the role of NER in its cytotoxicity, we used the fission yeast Schizosaccharomyces pombe as a model system. Treatment of S. pombe wild-type cells with trabectedin led to cell cycle delay and activation of the DNA damage checkpoint, indicating that the drug causes DNA damage in vivo. DNA damage induced by the drug is mostly caused by the NER protein, Rad13 (the fission yeast orthologue to human XPG), and is mainly repaired by homologous recombination. By constructing different rad13 mutants, we show that the DNA damage induced by trabectedin depends on a 46–amino acid region of Rad13 that is homologous to a DNA-binding region of human nuclease FEN-1. More specifically, an arginine residue in Rad13 (Arg961), conserved in FEN1 (Arg314), was found to be crucial for the drug's cytotoxicity. These results lead us to propose a model for the action of trabectedin in eukaryotic cells in which the formation of a Rad13/DNA-trabectedin ternary complex, stabilized by Arg961, results in cell death. (Cancer Res 2006; 66(16): 8155-62)
Ras-Associated Protein-1 Regulates Extracellular Signal-Regulated Kinase Activation and Migration in Melanoma Cells: Two Processes Important to Melanoma Tumorigenesis and Metastasis
Authors: Gao Ling , Feng Yunfeng , Bowers Regina , Becker-Hapak Michelle , Gardner Jennifer , Council Laurin , Linette Gerald , Zhao Haibo , Cornelius Lynn A. 
Published: August 2006

Abstract
Melanoma is one of the most devastating malignances with a rising incidence and lack of effective treatments for advanced disease. Constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and altered expression of αvβ3 integrin are critical for melanoma development and progression. Ras-associated protein-1 (Rap1), a Ras family member of the small GTPases, has emerged as a key mediator in these two important processes. In this study, we have shown Rap1 activation in cells derived from two human metastatic melanomas and also in three of seven cutaneous metastatic melanoma tissues. We found increased extracellular signal-regulated kinase (ERK) activity in the tumors with detected Rap1 activity that interestingly harbored neither BRAF nor N-Ras mutation, suggesting a role for Rap1 in ERK activation in vivo. We also showed Rap1 and ERK activation by both hepatocyte growth factor (HGF) and 8CPT-2Me-cAMP (an activator of Epac, a Rap1 guanine nucleotide exchange factor) in two human melanoma cell lines. In addition, the activation of ERK by HGF was reduced, at least in part, by small interfering RNAs against Rap1 and a dominant-negative Rap1. Finally, a functional role for Rap1 activation was shown by Rap1-induced αvβ3 integrin activation and consequent increased melanoma cell migration in vitro. Taken together, these results show that Rap1 is involved in the activation of MAPK pathway and integrin activation in human melanoma and suggest a potential role for Rap1 in melanoma tumorigenesis and metastasis. (Cancer Res 2006; 66(16): 7880-8)
Zebrafish as a “Biosensor”? Effects of Ionizing Radiation and Amifostine on Embryonic Viability and Development
Authors: Geiger Geoffrey A. , Parker Sharon E. , Beothy Andrew P. , Tucker Jennifer A. , Mullins Mary C. , Kao Gary D. 
Published: August 2006

AbstractThe zebrafish (Danio rerio) has emerged as a popular vertebrate model system for cancer and treatment-related research. Benefits include ease of care, rapid development, optical clarity of embryos, which allows visualization of major organ systems, and opportunities for genetic manipulation. However, specific parameters of radiation sensitivity have not been systematically documented. We investigated the effects of radiation and a radiomodifier on zebrafish viability and embryonic development. Embryos were exposed to γ-radiation (5, 10, or 20 Gy) at sequential times postfertilization and serially assessed for viability and morphologic abnormalities. As expected, lethality and morphologic perturbations were more pronounced earlier in embryogenesis and with higher radiation doses and were partially reversed by amifostine. The effects of radiation and concurrent treatment with amifostine on the developmental organization of the eye and brain were striking. Radiation resulted in hypocellularity and disorganization of the cellular layers of the retina, effects partially reversed by amifostine, as well as lens opacification. Radiation strikingly reduced the volume of brain, but the volume loss was substantially blocked by amifostine. Increased terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling signal was noted in both the irradiated eye and brain, but reduced by amifostine. Finally, irradiating embryos resulted in caspase activation detectable in 96-well microplates, which was proportional to the number of embryos and radiation dose; the degree of activation was markedly reduced by amifostine. These results together suggest the power and versatility of the zebrafish in assessing the effects of radiation and radiomodifiers on organ and tissue development. (Cancer Res 2006; 66(16): 8172-81)
Synergy of p53 and Rb Deficiency in a Conditional Mouse Model for Metastatic Prostate Cancer
Authors: Zhou Zongxiang , Flesken-Nikitin Andrea , Corney David C. , Wang Wei , Goodrich David W. , Roy-Burman Pradip , Nikitin Alexander Yu. 
Published: August 2006

Abstract
Pathways mediated by p53 and Rb are frequently altered in aggressive human cancers, including prostate carcinoma. To test directly the roles of p53 and Rb in prostate carcinogenesis, we have conditionally inactivated these genes in the prostate epithelium of the mouse. Inactivation of either p53 or Rb leads to prostatic intraepithelial neoplasia developing from the luminal epithelium by 600 days of age. In contrast, inactivation of both genes results in rapidly developing (median survival, 226 days) carcinomas showing both luminal epithelial and neuroendocrine differentiation. The resulting neoplasms are highly metastatic, resistant to androgen depletion from the early stage of development, and marked with multiple gene expression signatures commonly found in human prostate carcinomas. Interestingly, gains at 4qC3 and 4qD2.2 and loss at 14qA2-qD2 have been consistently found by comparative genomic hybridization. These loci contain such human cancer–related genes as Nfib, L-myc, and Nkx3.1, respectively. Our studies show a critical role for p53 and Rb deficiency in prostate carcinogenesis and identify likely secondary genetic alterations. The new genetically defined model should be particularly valuable for providing new molecular insights into the pathogenesis of human prostate cancer. (Cancer Res 2006; 66(16): 7889-98)