Abstract
The multifunctional roles of BRCA1 include its ability to regulate transcriptional processes that control differentiation at multiple levels, as well as functioning as a tumor suppressor. Data herein demonstrate that germline mutations in Brca1 impair luminal cell lineage and mammary development, with its deficiency converting ER-positive luminal tumors into basal-like cancers. Heterozygous mutations in Brca1 lead to downregulation of a number of luminal differentiation genes, explaining how it suppresses basal-like tumors, also highlighting its importance outside of its known highly publicized role in DNA repair.
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References
Bai F, Smith MD, Chan HL, Pei X-H . Germline mutation of Brca1 alters the fate of mammary luminal cells and causes luminal-to-basal mammary tumor transformation. Oncogene 2013; 32: 2715–2725.
Somasundaram K, Zhang H, Zeng Y-X, Houvras Y, Peng Y, Zhang H et al. Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiPl. Nature 1997; 389: 187–190.
Molyneux G, Geyer FC, Magnay FA, McCarthy A, Kendrick H, Natrajan R et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 2010; 7: 403–417.
Pei X-H, Bai F, Smith MD, Usary J, Fan C, Pai S-Y et al. CDK inhibitor p18INK4c is a downstream target of gata3 and restrains mammary luminal progenitor cell proliferation and tumorigenesis. Cancer Cell 2009; 15: 389–401.
Chen Y, Lee W-H, Chew HK . Emerging roles of BRCA1 in transcriptional regulation and DNA repair. J Cell Physiol 1999; 181: 385–392.
Taghavi N, Biramijamal F, Sotoudeh M, Khademi H, Malekzadeh R, Moaven O et al. p16INK4a hypermethylation and p53, p16 and MDM2 protein expression in esophageal squamous cell carcinoma. BMC Cancer 2010; 10: 138.
Drost R, Bouwman P, Rottenberg S, Boon U, Schut E, Klarenbeek S et al. BRCA1 ring function is essential for tumor suppression but dispensable for therapy resistance. Cancer Cell 2011; 20: 797–809.
Deans AJ, Khanna KK, McNees CJ, Mercurio C, Heierhorst J, McArthur GA . Cyclin-dependent kinase 2 functions in normal dna repair and is a therapeutic target in BRCA1-deficient cancers. Cancer Res 2006; 66: 8219–8226.
Morris JR, Boutell C, Keppler M, Densham R, Weekes D, Alamshah A et al. The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress. Nature 2009; 462: 886–890.
Coene ED, Gadelha C, White N, Malhas A, Thomas B, Shaw M et al. A novel role for BRCA1 in regulating breast cancer cell spreading and motility. J Cell Biol 2011; 192: 497–512.
Turner NC, Lord CJ, Iorns E, Brough R, Swift S, Elliott R et al. A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. EMBO J 2008; 27: 1368–1377.
Furuta S, Jiang X, Gu B, Cheng E, Chen PL, Lee WH . Depletion of BRCA1 impairs differentiation but enhances proliferation of mammary epithelial cells. Proc Natl Acad Sci USA 2005; 102: 9176–9181.
Marquis ST, Rajan JV, Wynshaw-Boris A, Xu J, Yin GY, Abel KJ et al. The developmental pattern of Brca1 expression implies a role in differentiation of the breast and other tissues. Nat Genet 1995; 11: 17–26.
Rajan JV, Wang M, Marquis ST, Chodosh LA . Brca2 is coordinately regulated with Brca1 during proliferation and differentiation in mammary epithelial cells. Proc Natl Acad Sci USA 1996; 93: 13078–13083.
Lane TF, Deng C, Elson A, Lyu MS, Kozak CA, Leder P . Expression of Brca1 is associated with terminal differentiation of ectodermally and mesodermally derived tissues in mice. Genes Dev 1995; 9: 2712–2722.
Kubista M, Rosner M, Kubista E, Bernaschek G, Hengstschlager M . Brca1 regulates in vitro differentiation of mammary epithelial cells. Oncogene 2002; 21: 4747–4756.
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Ng, T., Irshad, S. & Stebbing, J. BRCA1 mutations and luminal-basal transformation. Oncogene 32, 2712–2714 (2013). https://doi.org/10.1038/onc.2012.379
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DOI: https://doi.org/10.1038/onc.2012.379