ID Proteins Regulate Diverse Aspects of Cancer Progression and Provide Novel Therapeutic Opportunities
Authors: Radhika Nair, Wee Siang Teo, Vivek Mittal, Alexander Swarbrick
Journal: Molecular Therapy (2014)

The inhibitor of differentiation (ID) proteins are helix-loop-helix transcriptional repressors with established roles in stem cell self-renewal, lineage commitment, and niche interactions. While deregulated expression of ID proteins in cancer was identified more than a decade ago, emerging evidence has revealed a central role for ID proteins in neoplastic progression of multiple tumor types that often mirrors their function in physiological stem and progenitor cells. ID proteins are required for the maintenance of cancer stem cells, self-renewal, and proliferation in a range of malignancies. Furthermore, ID proteins promote metastatic dissemination through their role in remodeling the tumor microenvironment and by promoting tumor-associated endothelial progenitor cell proliferation and mobilization. Here, we discuss the latest findings in this area and the clinical opportunities that they provide. The inhibitor of differentiation (ID) proteins are helix-loop-helix transcriptional repressors with established roles in stem cell self-renewal, lineage commitment, and niche interactions. While deregulated expression of ID proteins in cancer was identified more than a decade ago, emerging evidence has revealed a central role for ID proteins in neoplastic progression of multiple tumor types that often mirrors their function in physiological stem and progenitor cells. ID proteins are required for the maintenance of cancer stem cells, self-renewal, and proliferation in a range of malignancies. Furthermore, ID proteins promote metastatic dissemination through their role in remodeling the tumor microenvironment and by promoting tumor-associated endothelial progenitor cell proliferation and mobilization. Here, we discuss the latest findings in this area and the clinical opportunities that they provide. The inhibitor of differentiation (ID) family of proteins are critical regulators in a wide range of developmental and cellular processes. They regulate stem cell homeostasis and fate commitment in various cell types, including neuronal,1Nam HS Benezra R High levels of Id1 expression define B1 type adult neural stem cells.Cell Stem Cell. 2009; 5: 515-526Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar hematopoietic,2Jankovic V Ciarrocchi A Boccuni P DeBlasio T Benezra R Nimer SD Id1 restrains myeloid commitment, maintaining the self-renewal capacity of hematopoietic stem cells.Proc Natl Acad Sci USA. 2007; 104: 1260-1265Crossref PubMed Scopus (0) Google Scholar,3Perry SS Zhao Y Nie L Cochrane SW Huang Z Sun XH Id1, but not Id3, directs long-term repopulating hematopoietic stem-cell maintenance.Blood. 2007; 110: 2351-2360Crossref PubMed Scopus (62) Google Scholar and embryonic4Romero-Lanman EE Pavlovic S Amlani B Chin Y Benezra R Id1 maintains embryonic stem cell self-renewal by up-regulation of Nanog and repression of Brachyury expression.Stem Cells Dev. 2012; 21: 384-393Crossref PubMed Scopus (0) Google Scholar cells, where they function by both inhibiting cell-autonomous differentiation programs4Romero-Lanman EE Pavlovic S Amlani B Chin Y Benezra R Id1 maintains embryonic stem cell self-renewal by up-regulation of Nanog and repression of Brachyury expression.Stem Cells Dev. 2012; 21: 384-393Crossref PubMed Scopus (0) Google Scholar and by coordinating the cell's interaction with the extracellular milieu and its niche.5Suh HC Ji M Gooya J Lee M Klarmann KD Keller JR Cell-nonautonomous function of Id1 in the hematopoietic progenitor cell niche.Blood. 2009; 114: 1186-1195Crossref PubMed Scopus (15) Google Scholar,6Niola F Zhao X Singh D Castano A Sullivan R Lauria M et al.Id proteins synchronize stemness and anchorage to the niche of neural stem cells.Nat Cell Biol. 2012; 14: 477-487Crossref PubMed Scopus (62) Google Scholar In this review, we will focus on recent discoveries demonstrating that these functions of IDs are retained by many cancers to promote proliferation and self-renewal and to facilitate signaling from the tumor microenvironment. The four members of the vertebrate ID family (ID1, ID2, ID3, and ID4) belong to the basic helix-loop-helix (bHLH) family of transcription factors. All four members share the highly conserved bHLH region and have similar molecular weights of between 13–20 kDa.7Lim RW Wu JM Molecular mechanisms regulating expression and function of transcription regulator inhibitor of differentiation 3.Acta Pharmacol Sin. 2005; 26: 1409-1420Crossref PubMed Scopus (0) Google Scholar,8Norton JD ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis.J Cell Sci. 2000; 113: 3897-3905Crossref PubMed Google Scholar Outside the HLH domain, there are extensive sequence differences among the four members of the ID proteins. Different members of the ID proteins are expressed in distinct expression patterns in a tissue-specific and stage-dependent manner, hence controlling different cellular and physiological processes.9Biggs J Murphy EV Israel MA A human Id-like helix-loop-helix protein expressed during early development.Proc Natl Acad Sci USA. 1992; 89: 1512-1516Crossref PubMed Google Scholar,10Riechmann V van Crüchten I Sablitzky F The expression pattern of Id4, a novel dominant negative helix-loop-helix protein, is distinct from Id1, Id2 and Id3.Nucleic Acids Res. 1994; 22: 749-755Crossref PubMed Google Scholar,11Sun XH Copeland NG Jenkins NA Baltimore D Id proteins Id1 and Id2 selectively inhibit DNA binding by one class of helix-loop-helix proteins.Mol Cell Biol. 1991; 11: 5603-5611Crossref PubMed Scopus (0) Google Scholar The bHLH transcription factors are key regulators of lineage- and tissue-specific gene expression and act as obligate dimers binding DNA through composite basic domains to regulate the transcription of target genes containing E-boxes (CANNTG) in their promoters. ID proteins dimerize with bHLH proteins, but because ID proteins lack a basic DNA-binding domain, ID-bHLH heterodimers fail to bind DNA, thereby inhibiting the transcriptional activity of the bHLH proteins. As such, ID proteins are dominant negative regulators of bHLH function.12Benezra R Davis RL Lockshon D Turner DL Weintraub H The protein Id: a negative regulator of helix-loop-helix DNA binding proteins.Cell. 1990; 61: 49-59Abstract Full Text PDF PubMed Scopus (1531) Google Scholar ID proteins interact with the ubiquitously expressed E protein transcription factors (E12, E47, E2-2, and HEB) which can act as homodimers (in B cells) or as heterodimers with tissue-restricted bHLH proteins such as MyoD (muscle) and NeuroD (nerve). A number of reports demonstrate noncanonical functions for ID proteins, including binding to non-HLH transcription factors such as Rb-family pocket proteins,13Lasorella A Iavarone A Israel MA Id2 specifically alters regulation of the cell cycle by tumor suppressor proteins.Mol Cell Biol. 1996; 16: 2570-2578Crossref PubMed Google Scholar Ets factors,14Ohtani N Zebedee Z Huot TJ Stinson JA Sugimoto M Ohashi Y et al.Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence.Nature. 2001; 409: 1067-1070Crossref PubMed Scopus (465) Google Scholar or RNA15Fontemaggi G Dell'Orso S Trisciuoglio D Shay T Melucci E Fazi F et al.The execution of the transcriptional axis mutant p53, E2F1 and ID4 promotes tumor neo-angiogenesis.Nat Struct Mol Biol. 2009; 16: 1086-1093Crossref PubMed Scopus (0) Google Scholar although the broader significance of these findings to ID protein biology is yet to be explored. The biochemical mechanisms of ID protein activity remain largely unelucidated and comprise an area of intensive investigation. ID family members exhibit unique spatio-temporal patterns of tissue expression during development16Jen Y Manova K Benezra R Each member of the Id gene family exhibits a unique expression pattern in mouse gastrulation and neurogenesis.Dev Dyn. 1997; 208: 92-106Crossref PubMed Scopus (168) Google Scholar and malignancy,17Perk J Gil-Bazo I Chin Y de Candia P Chen JJ Zhao Y et al.Reassessment of id1 protein expression in human mammary, prostate, and bladder cancers using a monospecific rabbit monoclonal anti-id1 antibody.Cancer Res. 2006; 66: 10870-10877Crossref PubMed Scopus (66) Google Scholar although evidence suggests biochemical redundancy in vitro.8Norton JD ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis.J Cell Sci. 2000; 113: 3897-3905Crossref PubMed Google Scholar The mechanisms governing ID protein expression are complex—an extensive body of literature shows that ID gene transcription is exquisitely sensitive to signals from the extracellular environment, including transforming growth factor-β (TGF-β),18Kowanetz M Valcourt U Bergström R Heldin CH Moustakas A Id2 and Id3 define the potency of cell proliferation and differentiation responses to transforming growth factor beta and bone morphogenetic protein.Mol Cell Biol. 2004; 24: 4241-4254Crossref PubMed Scopus (0) Google Scholar,19Kang Y Chen CR Massagué J A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells.Mol Cell. 2003; 11: 915-926Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar steroid hormones,20Lin CQ Singh J Murata K Itahana Y Parrinello S Liang SH et al.A role for Id-1 in the aggressive phenotype and steroid hormone response of human breast cancer cells.Cancer Res. 2000; 60: 1332-1340PubMed Google Scholar receptor tyrosine kinases,21Tam WF Gu TL Chen J Lee BH Bullinger L Fröhling S et al.Id1 is a common downstream target of oncogenic tyrosine kinases in leukemic cells.Blood. 2008; 112: 1981-1992Crossref PubMed Scopus (30) Google Scholar,22Bain G Cravatt CB Loomans C Alberola-Ila J Hedrick SM Murre C Regulation of the helix-loop-helix proteins, E2A and Id3, by the Ras-ERK MAPK cascade.Nat Immunol. 2001; 2: 165-171Crossref PubMed Scopus (0) Google Scholar and oncoproteins23Lasorella A Noseda M Beyna M Yokota Y Iavarone A Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins.Nature. 2000; 407: 592-598Crossref PubMed Scopus (409) Google Scholar (Figure 1). The stability of IDs is also tightly controlled by the APC/Cdh1 E3 ubiquitin ligase complex,24Lasorella A Stegmüller J Guardavaccaro D Liu G Carro MS Rothschild G et al.Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth.Nature. 2006; 442: 471-474Crossref PubMed Scopus (177) Google Scholar resulting in short half-lives for ID proteins in most tissues. In certain physiological and malignant stem cell populations, ID proteins are stabilized by the ubiquitin-specific peptidase 1 deubiquitinase which counters ubiquitin-mediated ID destruction.25Williams SA Maecker HL French DM Liu J Gregg A Silverstein LB et al.USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma.Cell. 2011; 146: 918-930Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar Ubiquitin-specific peptidase 1 is overexpressed in a subset of primary osteosarcomas, where it stabilizes ID1, ID2, and ID3, leading to repression of p21 and the osteogenic differentiation program.25Williams SA Maecker HL French DM Liu J Gregg A Silverstein LB et al.USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma.Cell. 2011; 146: 918-930Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar Analysis of clinical specimens has shown that high expression of ID proteins, particularly ID1, correlates with aggressive clinical behavior and poor patient outcome in many cancers (Table 1) Furthermore, data from our group shows ID1 expression is upregulated between primary breast cancers and their matched brain metastases (unpublished data) suggesting a functional role for ID1 in the metastatic process. However, analysis of ID1 expression in human cancers is complicated by several factors. ID1 can be expressed by rare neoplastic cells in subsets of breast,26Gupta GP Perk J Acharyya S de Candia P Mittal V Todorova-Manova K et al.ID genes mediate tumor reinitiation during breast cancer lung metastasis.Proc Natl Acad Sci USA. 2007; 104: 19506-19511Crossref PubMed Scopus (150) Google Scholar glioma,27Anido J Sáez-Borderías A Gonzàlez-Juncà A Rodón L Folch G Carmona MA et al.TGF-β Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma.Cancer Cell. 2010; 18: 655-668Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar and bladder17Perk J Gil-Bazo I Chin Y de Candia P Chen JJ Zhao Y et al.Reassessment of id1 protein expression in human mammary, prostate, and bladder cancers using a monospecific rabbit monoclonal anti-id1 antibody.Cancer Res. 2006; 66: 10870-10877Crossref PubMed Scopus (66) Google Scholar cancers, which can be difficult to identify using tissue microarrays. Furthermore, tumor-associated endothelial cells often show high ID1 expression, confounding expression analysis in whole tumor extracts.Table 1ID protein expression in primary human malignanciesID proteinTumor typeAlterationPrognosisReferenceID1BladderIncreasedPoor117Ding Y Wang G Ling MT Wong YC Li X Na Y et al.Significance of Id-1 up-regulation and its association with EGFR in bladder cancer cell invasion.Int J Oncol. 2006; 28: 847-854PubMed Google ScholarBrainIncreasedGood59Barrett LE Granot Z Coker C Iavarone A Hambardzumyan D Holland EC et al.Self-renewal does not predict tumor growth potential in mouse models of high-grade glioma.Cancer Cell. 2012; 21: 11-24Abstract Full Text Full Text PDF PubMed Scopus (98) Google ScholarBreastIncreasedPoor26Gupta GP Perk J Acharyya S de Candia P Mittal V Todorova-Manova K et al.ID genes mediate tumor reinitiation during breast cancer lung metastasis.Proc Natl Acad Sci USA. 2007; 104: 19506-19511Crossref PubMed Scopus (150) Google Scholar, 63Swarbrick A Roy E Allen T Bishop JM Id1 cooperates with oncogenic Ras to induce metastatic mammary carcinoma by subversion of the cellular senescence response.Proc Natl Acad Sci USA. 2008; 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11: 417Crossref PubMed Scopus (0) Google ScholarColon and rectalIncreasedPoor65O'Brien CA Kreso A Ryan P Hermans KG Gibson L Wang Y et al.ID1 and ID3 regulate the self-renewal capacity of human colon cancer-initiating cells through p21.Cancer Cell. 2012; 21: 777-792Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 120Wilson JW Deed RW Inoue T Balzi M Becciolini A Faraoni P et al.Expression of Id helix-loop-helix proteins in colorectal adenocarcinoma correlates with p53 expression and mitotic index.Cancer Res. 2001; 61: 8803-8810PubMed Google ScholarGastricIncreasedPoor121Yang HY Liu HL Liu GY Zhu H Meng QW Qu LD et al.Expression and prognostic values of Id-1 and Id-3 in gastric adenocarcinoma.J Surg Res. 2011; 167: 258-266Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 122Iwatsuki M Fukagawa T Mimori K Nakanishi H Ito S Ishii H et al.Bone marrow and peripheral blood expression of ID1 in human gastric carcinoma patients is a bona fide indicator of lymph node and peritoneal metastasis.Br J Cancer. 2009; 100: 1937-1942Crossref PubMed Scopus (0) Google ScholarHead and neckIncreasedPoor123Sun W Guo MM Han P Lin JZ Liang FY Tan GM et al.Id-1 and the p65 subunit of NF-κB promote migration of nasopharyngeal carcinoma cells and are correlated with poor prognosis.Carcinogenesis. 2012; 33: 810-817Crossref PubMed Scopus (0) Google ScholarKidneyIncreasedPoor124Li X Zhang Z Xin D Chua CW Wong YC Leung SC et al.Prognostic significance of Id-1 and its association with EGFR in renal cell cancer.Histopathology. 2007; 50: 484-490Crossref PubMed Scopus (0) Google ScholarLungIncreasedPoor125Bhattacharya R Kowalski J Larson AR Brock M Alani RM Id1 promotes tumor cell migration in nonsmall cell lung cancers.J Oncol. 2010; 2010: 856105Crossref PubMed Scopus (0) Google Scholar, 126Pillai S Rizwani W Li X Rawal B Nair S Schell MJ et al.ID1 facilitates the growth and metastasis of non-small cell lung cancer in response to nicotinic acetylcholine receptor and epidermal growth factor receptor signaling.Mol Cell Biol. 2011; 31: 3052-3067Crossref PubMed Scopus (34) Google Scholar, 127Castañon E Bosch-Barrera J López I Collado V Moreno M López-Picazo JM et al.Id1 and Id3 co-expression correlates with clinical outcome in stage III-N2 non-small cell lung cancer patients treated with definitive chemoradiotherapy.J Transl Med. 2013; 11: 13Crossref PubMed Scopus (15) Google Scholar, 128Ponz-Sarvisé M Nguewa PA Pajares MJ Agorreta J Lozano MD Redrado M et al.Inhibitor of differentiation-1 as a novel prognostic factor in NSCLC patients with adenocarcinoma histology and its potential contribution to therapy resistance.Clin Cancer Res. 2011; 17: 4155-4166Crossref PubMed Scopus (28) Google ScholarLeukemiaIncreasedPoor119Tobin NP Sims AH Lundgren KL Lehn S Landberg G Cyclin D1, Id1 and EMT in breast cancer.BMC Cancer. 2011; 11: 417Crossref PubMed Scopus (0) Google ScholarLiverIncreasedPoor129Ding R Han S Lu Y Guo C Xie H Zhang N et al.Overexpressed Id-1 is associated with patient prognosis and HBx expression in hepatitis B virus-related hepatocellular carcinoma.Cancer Biol Ther. 2010; 10: 299-307Crossref PubMed Google Scholar, 130Matsuda Y Yamagiwa S Takamura M Honda Y Ishimoto Y Ichida T et al.Overexpressed Id-1 is associated with a high risk of hepatocellular carcinoma development in patients with cirrhosis without transcriptional repression of p16.Cancer. 2005; 104: 1037-1044Crossref PubMed Scopus (0) Google ScholarNasopharyngealIncreasedPoor123Sun W Guo MM Han P Lin JZ Liang FY Tan GM et al.Id-1 and the p65 subunit of NF-κB promote migration of nasopharyngeal carcinoma cells and are correlated with poor prognosis.Carcinogenesis. 2012; 33: 810-817Crossref PubMed Scopus (0) Google ScholarEsophagealIncreasedPoor131Luo KJ Wen J Xie X Fu JH Luo RZ Wu QL et al.Prognostic relevance of Id-1 expression in patients with resectable esophageal squamous cell carcinoma.Ann Thorac Surg. 2012; 93: 1682-1688Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarOvarianIncreasedPoor132Schindl M Schoppmann SF Ströbel T Heinzl H Leisser C Horvat R et al.Level of Id-1 protein expression correlates with poor differentiation, enhanced malignant potential, and more aggressive clinical behavior of epithelial ovarian tumors.Clin Cancer Res. 2003; 9: 779-785PubMed Google ScholarPancreaticIncreasedPoor133Maruyama H Kleeff J Wildi S Friess H Büchler MW Israel MA et al.Id-1 and Id-2 are overexpressed in pancreatic cancer and in dysplastic lesions in chronic pancreatitis.Am J Pathol. 1999; 155: 815-822Abstract Full Text Full Text PDF PubMed Google ScholarProstaticIncreasedPoor75Zhang X Ling MT Wang Q Lau CK Leung SC Lee TK et al.Identification of a novel inhibitor of differentiation-1 (ID-1) binding partner, caveolin-1, and its role in epithelial-mesenchymal transition and resistance to apoptosis in prostate cancer cells.J Biol Chem. 2007; 282: 33284-33294Crossref PubMed Scopus (0) Google Scholar, 81Coppe JP Itahana Y Moore DH Bennington JL Desprez PY Id-1 and Id-2 proteins as molecular markers for human prostate cancer progression.Clin Cancer Res. 2004; 10: 2044-2051Crossref PubMed Scopus (0) Google Scholar, 134Sharma P Patel D Chaudhary J Id1 and Id3 expression is associated with increasing grade of prostate cancer: Id3 preferentially regulates CDKN1B.Cancer Med. 2012; 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Open table in a new tab ID, inhibitor of differentiation. In contrast to ID1, other ID proteins possess diverse patterns of expression and function in cancer. Recent data from several groups demonstrates that ID3 is a tumor suppressor in Burkitt's lymphoma, and is inactivated through somatic mutation in up to 68% of cases.28Love C Sun Z Jima D Li G Zhang J Miles R et al.The genetic landscape of mutations in Burkitt lymphoma.Nat Genet. 2012; 44: 1321-1325Crossref PubMed Scopus (0) Google Scholar,29Richter J Schlesner M Hoffmann S Kreuz M Leich E Burkhardt B ICGC MMML-Seq Project et al.Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing.Nat Genet. 2012; 44: 1316-1320Crossref PubMed Scopus (152) Google Scholar,30Schmitz R Young RM Ceribelli M Jhavar S Xiao W Zhang M et al.Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics.Nature. 2012; 490: 116-120Crossref PubMed Scopus (309) Google Scholar ID3 inactivation promotes tumor cell survival through ligand-independent signaling by the B-cell receptor to the PI3K pathway. Interestingly, ID3 is not mutated in other B-cell lymphomas, perhaps reflecting ID3's role in specific phases of B-cell maturation.29Richter J Schlesner M Hoffmann S Kreuz M Leich E Burkhardt B ICGC MMML-Seq Project et al.Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing.Nat Genet. 2012; 44: 1316-1320Crossref PubMed Scopus (152) Google Scholar Similarly, ID4 is epigenetically silenced through promoter hypermethylation in subsets of cancers, including human leukemia,31Yu L Liu C Vandeusen J Becknell B Dai Z Wu YZ et al.Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia.Nat Genet. 2005; 37: 265-274Crossref PubMed Scopus (0) Google Scholar,32Chen SS Claus R Lucas DM Yu L Qian J Ruppert AS et al.Silencing of the inhibitor of DNA binding protein 4 (ID4) contributes to the pathogenesis of mouse and human CLL.Blood. 2011; 117: 862-871Crossref PubMed Scopus (46) Google Scholar suggesting a tumor suppressive function. Conversely, ID4 acts as a proto-oncogene in serous ovarian cancer where it is genomically amplified, overexpressed, and required for SOC cell line proliferation.33Ren Y Cheung HW von Maltzhan G Agrawal A Cowley GS Weir BA et al.Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4.Sci Transl Med. 2012; 4: 147ra112Crossref PubMed Scopus (77) Google Scholar ID4 has been identified as a negative regulator of BRCA1 which is the most commonly mutated gene in familial breast and ovarian cancer.34Turner N Tutt A Ashworth A Hallmarks of 'BRCAness' in sporadic cancers.Nat Rev Cancer. 2004; 4: 814-819Crossref PubMed Scopus (897) Google Scholar In an unbiased ribozyme-based screen ID4 was discovered to inversely regulate expression of BRCA1 in an ovarian and breast cancer cell line.35Beger C Pierce LN Kruger M Marcusson EG Robbins JM Welcsh P et al.Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach.Proc Natl Acad Sci USA. 2001; 98: 130-135Crossref PubMed Scopus (175) Google Scholar In a separate study by Welcsh et al., overexpression of BRCA1 increases the expression level of ID4, suggesting a negative feed-back loop in BRCA1 signalling.36Welcsh PL Lee MK Gonzalez-Hernandez RM Black DJ Mahadevappa M Swisher EM et al.BRCA1 transcriptionally regulates genes involved in breast tumorigenesis.Proc Natl Acad Sci USA