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BRCA1 and BRCA2: different roles in a common pathway of genome protection

Nature Reviews Cancer volume 12, pages 68–78 (2012)Cite this article

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Abstract

The proteins encoded by the two major breast cancer susceptibility genes, BRCA1 and BRCA2, work in a common pathway of genome protection. However, the two proteins work at different stages in the DNA damage response (DDR) and in DNA repair. BRCA1 is a pleiotropic DDR protein that functions in both checkpoint activation and DNA repair, whereas BRCA2 is a mediator of the core mechanism of homologous recombination. The links between the two proteins are not well understood, but they must exist to explain the marked similarity of human cancer susceptibility that arises with germline mutations in these genes. As discussed here, the proteins work in concert to protect the genome from double-strand DNA damage during DNA replication.

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Figure 1: Molecular mechanisms of the DNA damage response.
Figure 2: BRCA1 and BRCA2 functional domains.
Figure 3: Homologous recombination at different types of DNA damage.
Figure 4: BRCA-deficient cells accumulate chromatid breaks and chromatid exchanges.

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References

  1. Foulkes, W. D. Molecular origins of cancer: inherited susceptibility to common cancers. N. Engl. J. Med. 359, 2143–2153 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Schlacher, K. et al. Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145, 529–542 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Futreal, P. A. et al. A census of human cancer genes. Nature Rev. Cancer 4, 177–183 (2004).

    Article  CAS  Google Scholar 

  4. Rahman, N. & Stratton, M. R. The genetics of breast cancer susceptibility. Annu. Rev. Genet. 32, 95–121 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Huen, M. S., Sy, S. M. & Chen, J. BRCA1 and its toolbox for the maintenance of genome integrity. Nature Rev. Mol. Cell Biol. 11, 138–148 (2010).

    Article  CAS  Google Scholar 

  6. Deng, C. X. & Brodie, S. G. Roles of BRCA1 and its interacting proteins. Bioessays 22, 728–737 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Friedman, L. S. et al. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nature Genet. 8, 399–404 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Couch, F. J. & Weber, B. L. Mutations and polymorphisms in the familial early-onset breast cancer (BRCA1) gene. Breast Cancer Information Core. Hum. Mutat. 8, 8–18 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Shattuck-Eidens, D. et al. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. JAMA 273, 535–541 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Wu, L. C. et al. Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nature Genet. 14, 430–440 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Sato, K. et al. Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin ligase. J. Biol. Chem. 279, 30919–30922 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Nishikawa, H. et al. Mass spectrometric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCA1-BARD1 ubiquitin ligase. J. Biol. Chem. 279, 3916–3924 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Yu, X., Fu, S., Lai, M., Baer, R. & Chen, J. BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev. 20, 1721–1726 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yun, M. H. & Hiom, K. CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle. Nature 459, 460–463 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mohammad, D. H. & Yaffe, M. B. 14-3-3 proteins, FHA domains and BRCT domains in the DNA damage response. DNA Repair 8, 1009–1017 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sy, S. M., Huen, M. S. & Chen, J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc. Natl Acad. Sci. USA 106, 7155–7160 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang, F., Fan, Q., Ren, K. & Andreassen, P. R. PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. Mol. Cancer Res. 7, 1110–1118 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang, F. et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr. Biol. 19, 524–529 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang, B. et al. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316, 1194–1198 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kim, H., Chen, J. & Yu, X. Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science 316, 1202–1205 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Kim, H., Huang, J. & Chen, J. CCDC98 is a BRCA1-BRCT domain-binding protein involved in the DNA damage response. Nature Struct. Mol. Biol. 14, 710–715 (2007).

    Article  CAS  Google Scholar 

  22. Yu, X., Wu, L. C., Bowcock, A. M., Aronheim, A. & Baer, R. The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J. Biol. Chem. 273, 25388–25392 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Chen, L., Nievera, C. J., Lee, A. Y. & Wu, X. Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair. J. Biol. Chem. 283, 7713–7720 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Kim, S. S. et al. Uterus hyperplasia and increased carcinogen-induced tumorigenesis in mice carrying a _targeted mutation of the Chk2 phosphorylation site in Brca1. Mol. Cell. Biol. 24, 9498–9507 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang, J. et al. Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair. Mol. Cell. Biol. 24, 708–718 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chang, S., Biswas, K., Martin, B. K., Stauffer, S. & Sharan, S. K. Expression of human BRCA1 variants in mouse ES cells allows functional analysis of BRCA1 mutations. J. Clin. Invest. 119, 3160–3171 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhong, Q., Boyer, T. G., Chen, P. L. & Lee, W. H. Deficient nonhomologous end-joining activity in cell-free extracts from Brca1-null fibroblasts. Cancer Res. 62, 3966–3970 (2002).

    CAS  PubMed  Google Scholar 

  28. Zhong, Q., Chen, C. F., Chen, P. L. & Lee, W. H. BRCA1 facilitates microhomology-mediated end joining of DNA double strand breaks. J. Biol. Chem. 277, 28641–28647 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Moynahan, M. E., Chiu, J. W., Koller, B. H. & Jasin, M. Brca1 controls homology-directed DNA repair. Mol. Cell 4, 511–518 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Snouwaert, J. N. et al. BRCA1 deficient embryonic stem cells display a decreased homologous recombination frequency and an increased frequency of non-homologous recombination that is corrected by expression of a brca1 transgene. Oncogene 18, 7900–7907 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Wang, H. et al. Nonhomologous end-joining of ionizing radiation-induced DNA double-stranded breaks in human tumor cells deficient in BRCA1 or BRCA2. Cancer Res. 61, 270–277 (2001).

    CAS  PubMed  Google Scholar 

  32. Fu, Y. P. et al. Breast cancer risk associated with genotypic polymorphism of the nonhomologous end-joining genes: a multigenic study on cancer susceptibility. Cancer Res. 63, 2440–2446 (2003).

    CAS  PubMed  Google Scholar 

  33. Paull, T. T., Cortez, D., Bowers, B., Elledge, S. J. & Gellert, M. Direct DNA binding by Brca1. Proc. Natl Acad. Sci. USA 98, 6086–6091 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wei, L. et al. Rapid recruitment of BRCA1 to DNA double-strand breaks is dependent on its association with Ku80. Mol. Cell. Biol. 28, 7380–7393 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bunting, S. F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stark, J. M., Pierce, A. J., Oh, J., Pastink, A. & Jasin, M. Genetic steps of mammalian homologous repair with distinct mutagenic consequences. Mol. Cell. Biol. 24, 9305–9316 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Siliciano, J. D. et al. DNA damage induces phosphorylation of the amino terminus of p53. Genes Dev. 11, 3471–3481 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Fabbro, M. et al. BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage. J. Biol. Chem. 279, 31251–31258 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Xu, B., Kim, S. & Kastan, M. B. Involvement of Brca1 in S-phase and G2-phase checkpoints after ionizing irradiation. Mol. Cell. Biol. 21, 3445–3450 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Greenberg, R. A. et al. Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes. Genes Dev. 20, 34–46 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Moynahan, M. E., Pierce, A. J. & Jasin, M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol. Cell 7, 263–272 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Yang, H. et al. BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science 297, 1837–1848 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Li, J. et al. DSS1 is required for the stability of BRCA2. Oncogene 25, 1186–1194 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Kojic, M., Yang, H., Kostrub, C. F., Pavletich, N. P. & Holloman, W. K. The BRCA2-interacting protein DSS1 is vital for DNA repair, recombination, and genome stability in Ustilago maydis. Mol. Cell 12, 1043–1049 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Kristensen, C. N., Bystol, K. M., Li, B., Serrano, L. & Brenneman, M. A. Depletion of DSS1 protein disables homologous recombinational repair in human cells. Mutat. Res. 694, 60–64 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Yang, H., Li, Q., Fan, J., Holloman, W. K. & Pavletich, N. P. The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA–ssDNA junction. Nature 433, 653–657 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Powell, S. N., Willers, H. & Xia, F. BRCA2 keeps Rad51 in line. High-fidelity homologous recombination prevents breast and ovarian cancer? Mol. Cell 10, 1262–1263 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Thorslund, T. et al. The breast cancer tumor suppressor BRCA2 promotes the specific _targeting of RAD51 to single-stranded DNA. Nature Struct. Mol. Biol. 17, 1263–1265 (2010).

    Article  CAS  Google Scholar 

  49. Venkitaraman, A. R. Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment. Annu. Rev. Pathol. 4, 461–487 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Pellegrini, L. et al. Insights into DNA recombination from the structure of a RAD51–BRCA2 complex. Nature 420, 287–293 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Wooster, R. et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 378, 789–792 (1995).

    Article  CAS  PubMed  Google Scholar 

  52. Carreira, A. et al. The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51. Cell 136, 1032–1043 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Esashi, F. et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 434, 598–604 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Ayoub, N. et al. The carboxyl terminus of Brca2 links the disassembly of Rad51 complexes to mitotic entry. Curr. Biol. 19, 1075–1085 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Saeki, H. et al. Suppression of the DNA repair defects of BRCA2-deficient cells with heterologous protein fusions. Proc. Natl Acad. Sci. USA 103, 8768–8773 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Esashi, F., Galkin, V. E., Yu, X., Egelman, E. H. & West, S. C. Stabilization of RAD51 nucleoprotein filaments by the C-terminal region of BRCA2. Nature Struct. Mol. Biol. 14, 468–474 (2007).

    Article  CAS  Google Scholar 

  57. Petalcorin, M. I., Sandall, J., Wigley, D. B. & Boulton, S. J. CeBRC-2 stimulates D-loop formation by RAD-51 and promotes DNA single-strand annealing. J. Mol. Biol. 361, 231–242 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Jensen, R. B., Carreira, A. & Kowalczykowski, S. C. Purified human BRCA2 stimulates RAD51-mediated recombination. Nature 467, 678–683 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Liu, J., Doty, T., Gibson, B. & Heyer, W. D. Human BRCA2 protein promotes RAD51 filament formation on RPA-covered single-stranded DNA. Nature Struct. Mol. Biol. 17, 1260–1262 (2010).

    Article  CAS  Google Scholar 

  60. Yuan, S. S. et al. BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo. Cancer Res. 59, 3547–3551 (1999).

    CAS  PubMed  Google Scholar 

  61. Patel, K. J. et al. Involvement of Brca2 in DNA repair. Mol. Cell 1, 347–357 (1998).

    Article  CAS  PubMed  Google Scholar 

  62. Daniels, M. J., Wang, Y., Lee, M. & Venkitaraman, A. R. Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science 306, 876–879 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Evers, B. & Jonkers, J. Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects. Oncogene 25, 5885–5897 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Deng, C. X. & Scott, F. Role of the tumor suppressor gene Brca1 in genetic stability and mammary gland tumor formation. Oncogene 19, 1059–1064 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Tsuzuki, T. et al. _targeted disruption of the Rad51 gene leads to lethality in embryonic mice. Proc. Natl Acad. Sci. USA 93, 6236–6240 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Stefansson, O. A. et al. Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes. Breast Cancer Res. 11, R47 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Willers, H. et al. Utility of DNA repair protein foci for the detection of putative BRCA1 pathway defects in breast cancer biopsies. Mol. Cancer Res. 7, 1304–1309 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Oliver, A. W., Swift, S., Lord, C. J., Ashworth, A. & Pearl, L. H. Structural basis for recruitment of BRCA2 by PALB2. EMBO Rep. 10, 990–996 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Xia, B. et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol. Cell 22, 719–729 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Nagaraju, G. & Scully, R. Minding the gap: the underground functions of BRCA1 and BRCA2 at stalled replication forks. DNA Repair 6, 1018–1031 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. McPherson, J. P. et al. A role for Brca1 in chromosome end maintenance. Hum. Mol. Genet. 15, 831–838 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Deng, C. X. & Brodie, S. G. Knockout mouse models and mammary tumorigenesis. Semin. Cancer Biol. 11, 387–394 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Alter, B. P. & Kupfer, G. Fanconi anemia. GeneReviews [online], (2011).

  74. Feng, Z. et al. Rad52 inactivation is synthetically lethal with BRCA2 deficiency. Proc. Natl Acad. Sci. USA 108, 686–691 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Hellebrand, H. et al. Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer. Hum. Mutat. 32, e2176–e2188 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Gowen, L. C., Johnson, B. L., Latour, A. M., Sulik, K. K. & Koller, B. H. Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nature Genet. 12, 191–194 (1996).

    Article  CAS  PubMed  Google Scholar 

  77. Cressman, V. L. et al. Mammary tumor formation in p53- and BRCA1-deficient mice. Cell Growth Differ. 10, 1–10 (1999).

    CAS  PubMed  Google Scholar 

  78. Jonkers, J. et al. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nature Genet. 29, 418–425 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. King, T. A. et al. Heterogenic loss of the wild-type BRCA allele in human breast tumorigenesis. Ann. Surg. Oncol. 14, 2510–2518 (2007).

    Article  PubMed  Google Scholar 

  80. Skoulidis, F. et al. Germline Brca2 heterozygosity promotes KrasG12D-driven carcinogenesis in a murine model of familial pancreatic cancer. Cancer Cell 18, 499–509 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Thorlacius, S. et al. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nature Genet. 13, 117–119 (1996).

    Article  CAS  PubMed  Google Scholar 

  82. Meek, D. W. Tumour suppression by p53: a role for the DNA damage response? Nature Rev. Cancer 9, 714–723 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Ramus, S. J. et al. Increased frequency of TP53 mutations in BRCA1 and BRCA2 ovarian tumours. Genes Chromosomes Cancer 25, 91–96 (1999).

    Article  CAS  PubMed  Google Scholar 

  84. Rowley, M. et al. Inactivation of Brca2 promotes Trp53-associated but inhibits KrasG12D-dependent pancreatic cancer development in mice. Gastroenterology 140, 1303–1313.e3 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. McAllister, K. A. et al. Spontaneous and irradiation-induced tumor susceptibility in BRCA2 germline mutant mice and cooperative effects with a p53 germline mutation. Toxicol. Pathol. 34, 187–198 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Liu, X. et al. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc. Natl Acad. Sci. USA 104, 12111–12116 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Schuyer, M. & Berns, E. M. Is TP53 dysfunction required for BRCA1-associated carcinogenesis? Mol. Cell. Endocrinol. 155, 143–152 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Hakem, R., de la Pompa, J. L., Elia, A., Potter, J. & Mak, T. W. Partial rescue of Brca15–6 early embryonic lethality by p53 or p21 null mutation. Nature Genet. 16, 298–302 (1997).

    Article  CAS  PubMed  Google Scholar 

  89. Bouwman, P. et al. Loss of p53 partially rescues embryonic development of Palb2 knockout mice but does not foster haploinsufficiency of Palb2 in tumour suppression. J. Pathol. 224, 10–21 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Cheung, A. M. et al. Loss of Brca2 and p53 synergistically promotes genomic instability and deregulation of T-cell apoptosis. Cancer Res. 62, 6194–6204 (2002).

    CAS  PubMed  Google Scholar 

  91. Crook, T. et al. p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours. Oncogene 17, 1681–1689 (1998).

    Article  CAS  PubMed  Google Scholar 

  92. Smith, P. D. et al. Novel p53 mutants selected in BRCA-associated tumours which dissociate transformation suppression from other wild-type p53 functions. Oncogene 18, 2451–2459 (1999).

    Article  CAS  PubMed  Google Scholar 

  93. Cao, L. et al. ATM-Chk2-p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency. EMBO J. 25, 2167–2177 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Tommiska, J. et al. The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer. Oncogene 27, 2501–2506 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Sullivan, A. et al. Concomitant inactivation of p53 and Chk2 in breast cancer. Oncogene 21, 1316–1324 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Fan, S. et al. BRCA1 inhibition of estrogen receptor signaling in transfected cells. Science 284, 1354–1356 (1999).

    Article  CAS  PubMed  Google Scholar 

  97. Somasundaram, K. et al. Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1. Nature 389, 187–190 (1997).

    Article  CAS  PubMed  Google Scholar 

  98. Zhu, Q. et al. BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. Nature 477, 179–184 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sipe, H. J. Jr, Jordan, S. J., Hanna, P. M. & Mason, R. P. The metabolism of 17β-estradiol by lactoperoxidase: a possible source of oxidative stress in breast cancer. Carcinogenesis 15, 2637–2643 (1994).

    Article  CAS  PubMed  Google Scholar 

  100. Malins, D. C., Holmes, E. H., Polissar, N. L. & Gunselman, S. J. The etiology of breast cancer. Characteristic alteration in hydroxyl radical-induced DNA base lesions during oncogenesis with potential for evaluating incidence risk. Cancer 71, 3036–3043 (1993).

    Article  CAS  PubMed  Google Scholar 

  101. Lavigne, J. A. et al. The effects of catechol-O-methyltransferase inhibition on estrogen metabolite and oxidative DNA damage levels in estradiol-treated MCF-7 cells. Cancer Res. 61, 7488–7494 (2001).

    CAS  PubMed  Google Scholar 

  102. Hamada, J. et al. Increased oxidative DNA damage in mammary tumor cells by continuous epidermal growth factor stimulation. J. Natl Cancer Inst. 93, 214–219 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Armes, J. E. et al. Distinct molecular pathogeneses of early-onset breast cancers in BRCA1 and BRCA2 mutation carriers: a population-based study. Cancer Res. 59, 2011–2017 (1999).

    CAS  PubMed  Google Scholar 

  104. Comen, E. et al. Relative contributions of BRCA1 and BRCA2 mutations to “triple-negative” breast cancer in Ashkenazi Women. Breast Cancer Res. Treat. 129, 185–190 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Sorlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869–10874 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bane, A. L. et al. BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays. Am. J. Surg. Pathol. 31, 121–128 (2007).

    Article  PubMed  Google Scholar 

  107. Holstege, H. et al. BRCA1-mutated and basal-like breast cancers have similar aCGH profiles and a high incidence of protein truncating TP53 mutations. BMC Cancer 10, 654 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Liu, Z., Wu, J. & Yu, X. CCDC98 _targets BRCA1 to DNA damage sites. Nature Struct. Mol. Biol. 14, 716–720 (2007).

    Article  CAS  Google Scholar 

  109. Sobhian, B. et al. RAP80 _targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316, 1198–1202 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Cantor, S. B. et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105, 149–160 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Cortez, D., Wang, Y., Qin, J. & Elledge, S. J. Requirement of ATM-dependent phosphorylation of Brca1 in the DNA damage response to double-strand breaks. Science 286, 1162–1166 (1999).

    Article  CAS  PubMed  Google Scholar 

  112. Xu, B., O'Donnell, A. H., Kim, S. T. & Kastan, M. B. Phosphorylation of serine 1387 in Brca1 is specifically required for the Atm-mediated S-phase checkpoint after ionizing irradiation. Cancer Res. 62, 4588–4591 (2002).

    CAS  PubMed  Google Scholar 

  113. Krainer, M. et al. Differential contributions of BRCA1 and BRCA2 to early-onset breast cancer. N. Engl. J. Med. 336, 1416–1421 (1997).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are supported by grants from the US National Cancer Institute and the Susan G. Komen For The Cure foundation.

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  1. Jarin Chun and Simon N. Powell are at the Molecular Biology Program and Department of Radiation Oncology, Rohini Roy, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.,

    Rohini Roy, Jarin Chun & Simon N. Powell

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Roy, R., Chun, J. & Powell, S. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer 12, 68–78 (2012). https://doi.org/10.1038/nrc3181

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