Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

BRCA1 and BRCA2: 1994 and beyond

Nature Reviews Cancer volume 4, pages 665–676 (2004)Cite this article

Key Points

  • In the ten years since the discovery of BRCA1 and BRCA2, genetic testing for breast and ovarian cancer susceptibility has become integrated into the practice of clinical oncology.

  • Attempts to identify a third breast cancer susceptibility locus (BRCA3) have so far been unsuccessful. This is probably because no single gene can account for the remainder of families that show a high incidence of breast cancer that is not associated with BRCA1 or BRCA2.

  • In general, the genes that have been identified as being associated with hereditary breast cancer (BRCA1, BRCA2, TP53, CHK2 and ATM) are involved in the maintenance of genomic integrity and DNA repair.

  • The risk of developing cancer is not identical for all carriers of BRCA1 and BRCA2 mutations. Risk can be influenced by allelic heterogeneity, modifier genes, and environmental and hormonal cofactors.

Abstract

The discovery of the first gene associated with hereditary breast cancer, BRCA1, was anticipated to greatly increase our understanding of both hereditary and sporadic forms of breast cancer, and to lead to therapeutic and preventive breakthroughs. Much has been learned during the past decade about the genetic epidemiology of breast cancer, the ethnic distribution and clinical consequences of BRCA1 and BRCA2 mutations, and the central role of DNA repair in breast cancer susceptibility. The ability to translate this knowledge into novel treatments, however, remains elusive.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: BRCA1 and BRCA2 functional domains, and selected binding partners.
Figure 2: The BRCA1 network.

Similar content being viewed by others

References

  1. Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).

    CAS  PubMed  Google Scholar 

  2. Hall, J. M. et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684–1689 (1990).

    CAS  PubMed  Google Scholar 

  3. Stratton, M. R. et al. Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q. Nature Genet. 7, 103–107 (1994).

    CAS  PubMed  Google Scholar 

  4. Wooster, R. et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12–13. Science 265, 2088–2090 (1994).

    CAS  PubMed  Google Scholar 

  5. Wooster, R. et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 378, 789–792 (1995). These five papers describe the localization and identification of BRCA1 and BRCA2 , which was the result of years of collaborative effort from numerous laboratories around the world.

    CAS  PubMed  Google Scholar 

  6. Collins, F. S. BRCA1 — lots of mutations, lots of dilemmas. N. Engl. J. Med. 334, 186–188 (1996).

    CAS  PubMed  Google Scholar 

  7. Lerman, C. et al. BRCA1 testing in families with hereditary breast–ovarian cancer. A prospective study of patient decision making and outcomes. JAMA 275, 1885–1892 (1996).

    CAS  PubMed  Google Scholar 

  8. Rebbeck, T. R. et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N. Engl. J. Med. 346, 1616–1622 (2002).

    PubMed  Google Scholar 

  9. Rebbeck, T. R. et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J. Clin. Oncol. 22, 1055–1062 (2004).

    PubMed  Google Scholar 

  10. Liede, A. & Narod, S. A. Hereditary breast and ovarian cancer in Asia: genetic epidemiology of BRCA1 and BRCA2. Hum. Mutat. 20, 413–424 (2002).

    CAS  PubMed  Google Scholar 

  11. Mancuso, C. et al. Ethnicity, but not cancer family history, is related to response to a population-based mailed questionnaire. Ann. Epidemiol. 14, 36–43 (2004).

    PubMed  Google Scholar 

  12. Simard, J. et al. Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nature Genet. 8, 392–398 (1994).

    CAS  PubMed  Google Scholar 

  13. Castilla, L. H. et al. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nature Genet. 8, 387–391 (1994).

    CAS  PubMed  Google Scholar 

  14. 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).

    CAS  PubMed  Google Scholar 

  15. Hogervorst, F. B. et al. Rapid detection of BRCA1 mutations by the protein truncation test. Nature Genet. 10, 208–212 (1995).

    CAS  PubMed  Google Scholar 

  16. Orita, M., Iwahana, H., Kanazawa, H., Hayashi, K. & Sekiya, T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc. Natl Acad. Sci. USA 86, 2766–2770 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Borresen, A. L., Hovig, E. & Brogger, A. Detection of base mutations in genomic DNA using denaturing gradient gel electrophoresis (DGGE) followed by transfer and hybridization with gene-specific probes. Mutat. Res. 202, 77–83 (1988).

    CAS  PubMed  Google Scholar 

  18. Wagner, T. et al. Denaturing high-performance liquid chromatography detects reliably BRCA1 and BRCA2 mutations. Genomics 62, 369–376 (1999).

    CAS  PubMed  Google Scholar 

  19. Andrulis, I. L. et al. Comparison of DNA- and RNA-based methods for detection of truncating BRCA1 mutations. Hum. Mutat. 20, 65–73 (2002).

    CAS  PubMed  Google Scholar 

  20. Eng, C. et al. Interpreting epidemiological research: blinded comparison of methods used to estimate the prevalence of inherited mutations in BRCA1. J. Med. Genet. 38, 824–833 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Narod, S. A. et al. Genetic heterogeneity of breast–ovarian cancer revisited. Breast Cancer Linkage Consortium. Am. J. Hum. Genet. 57, 957–958 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Gad, S. et al. Color bar coding the BRCA1 gene on combed DNA: a useful strategy for detecting large gene rearrangements. Genes Chromosom. Cancer 31, 75–84 (2001).

    CAS  PubMed  Google Scholar 

  23. Gad, S. et al. Bar code screening on combed DNA for large rearrangements of the BRCA1 and BRCA2 genes in French breast cancer families. J. Med. Genet. 39, 817–821 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Puget, N. et al. Screening for germ-line rearrangements and regulatory mutations in BRCA1 led to the identification of four new deletions. Cancer Res. 59, 455–461 (1999).

    CAS  PubMed  Google Scholar 

  25. Rohlfs, E. M. et al. An Alu-mediated 7.1 kb deletion of BRCA1 exons 8 and 9 in breast and ovarian cancer families that results in alternative splicing of exon 10. Genes Chromosom. Cancer 28, 300–307 (2000).

    CAS  PubMed  Google Scholar 

  26. Puget, N. et al. A 1-kb Alu-mediated germ-line deletion removing BRCA1 exon 17. Cancer Res. 57, 828–831 (1997).

    CAS  PubMed  Google Scholar 

  27. Scully, R. et al. Genetic analysis of BRCA1 function in a defined tumor cell line. Mol. Cell 4, 1093–1099 (1999).

    CAS  PubMed  Google Scholar 

  28. Hayes, F., Cayanan, C., Barilla, D. & Monteiro, A. N. Functional assay for BRCA1: mutagenesis of the COOH-terminal region reveals critical residues for transcription activation. Cancer Res. 60, 2411–2418 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Humphrey, J. S. et al. Human BRCA1 inhibits growth in yeast: potential use in diagnostic testing. Proc. Natl Acad. Sci. USA 94, 5820–5825 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Oddoux, C. et al. The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1 percent. Nature Genet. 14, 188–190 (1996).

    CAS  PubMed  Google Scholar 

  31. Kauff, N. D. et al. Incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families. J. Med. Genet. 39, 611–614 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Phelan, C. M. et al. A low frequency of non-founder BRCA1 mutations in Ashkenazi Jewish breast-ovarian cancer families. Hum. Mutat. 20, 352–357 (2002).

    CAS  PubMed  Google Scholar 

  33. Tulinius, H. et al. The effect of a single BRCA2 mutation on cancer in Iceland. J. Med. Genet. 39, 457–462 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Gorski, B. et al. A high proportion of founder BRCA1 mutations in Polish breast cancer families. Int. J. Cancer 110, 683–686 (2004).

    CAS  PubMed  Google Scholar 

  35. Risch, H. A. et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am. J. Hum. Genet. 68, 700–710 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Thompson, D. & Easton, D. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am. J. Hum. Genet. 68, 410–419 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Edwards, S. M. et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am. J. Hum. Genet. 72, 1–12 (2003).

    CAS  PubMed  Google Scholar 

  38. Struewing, J. P. et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N. Engl. J. Med. 336, 1401–1408 (1997).

    CAS  PubMed  Google Scholar 

  39. Warner, E. et al. Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J. Natl Cancer Inst. 91, 1241–1247 (1999).

    CAS  PubMed  Google Scholar 

  40. Tonin, P. et al. Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nature Med. 2, 1183–1196 (1996).

    Google Scholar 

  41. Narod, S. A. Modifiers of risk of hereditary breast and ovarian cancer. Nature Rev. Cancer 2, 113–123 (2002).

    Google Scholar 

  42. Meijers-Heijboer, H. et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N. Engl. J. Med. 345, 159–164 (2001).

    CAS  PubMed  Google Scholar 

  43. Kauff, N. D. et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N. Engl. J. Med. 346, 1609–1615 (2002).

    PubMed  Google Scholar 

  44. Rebbeck, T. R. et al. Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J. Natl Cancer Inst. 91, 1475–1479 (1999).

    CAS  PubMed  Google Scholar 

  45. Scully, R. & Livingston, D. M. In search of the tumour-suppressor functions of BRCA1 and BRCA2. Nature 408, 429–432 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Venkitaraman, A. R. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108, 171–182 (2002).

    CAS  PubMed  Google Scholar 

  47. Venkitaraman, A. R. Tracing the network connecting BRCA and Fanconi anaemia proteins. Nature Rev. Cancer 4, 266–276 (2004).

    CAS  Google Scholar 

  48. Scully, R. et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88, 265–275 (1997).

    CAS  PubMed  Google Scholar 

  49. Sharan, S. K. et al. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386, 804–810 (1997).

    CAS  PubMed  Google Scholar 

  50. Mizuta, R. et al. RAB22 and RAB163/mouse BRCA2-proteins that specifically interact with the rad51 protein. Proc. Natl Acad. Sci. USA 94, 6927–6932 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Wong, A. K., Pero, R., Ormonde, P. A., Tavtigian, S. V. & Bartel, P. L. RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2. J. Biol. Chem. 272, 31941–31944 (1997). References 48–51 show that interactions between BRCA1, BRCA2 and RAD51 are crucial elements of the coordinated response to DNA damage, and illustrate the consequences of the disruption of these relationships.

    CAS  PubMed  Google Scholar 

  52. Moynahan, M. E., Cui, T. Y. & Jasin, M. Homology-directed DNA repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res. 61, 4842–4850 (2001).

    CAS  PubMed  Google Scholar 

  53. Tassone, P. et al. BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells. Br. J. Cancer 88, 1285–1291 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Yuan, S. S. F. 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 

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

    CAS  PubMed  Google Scholar 

  56. Zhong, Q. et al. Association of BRCA1 with the hRad50–hMre11–p95 complex and the DNA damage response. Science 285, 747–750 (1999).

    CAS  PubMed  Google Scholar 

  57. Le Page, F. et al. BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells. Cancer Res. 60, 5548–5552 (2000).

    CAS  PubMed  Google Scholar 

  58. Hartman, A. R., Ford, J. M. BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair. Nature Genet. 32, 180–184 (2002).

    CAS  PubMed  Google Scholar 

  59. Wang, Y. et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 14, 927–939 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Callebaut, I. & Mornon, J. P. From BRCA1 to RAP1: a widespread BRCT module closely associated with DNA repair. FEBS Lett. 400, 25–30 (1997).

    CAS  PubMed  Google Scholar 

  61. Xu, X. et al. Centrosome amplification and a defective G2–M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol. Cell 3, 389–395 (1999).

    CAS  PubMed  Google Scholar 

  62. Hakem, R. et al. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell 85, 1009–1023 (1996).

    CAS  PubMed  Google Scholar 

  63. Hakem, R., de la Pompa, J. L., Elia, A., Potter, J. & Mak, T. W. Partial rescue of Brca1 (5-6) early embryonic lethality by p53 or p21 null mutation. Nature Genet. 16, 298–302 (1997). References 62 and 63 show that complete loss of BRCA1 protein in the mouse inhibits development, but can be partially rescued by deletion of the genes that encode its effector proteins.

    CAS  PubMed  Google Scholar 

  64. Tirkkonen, M. et al. Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. Cancer Res. 57, 1222–1227 (1997).

    CAS  PubMed  Google Scholar 

  65. Wessels, L. F. A. et al. Molecular classification of breast carcinomas by comparative genomic hybridization: a specific somatic genetic profile for BRCA1 tumors. Cancer Res. 62, 7110–7117 (2002).

    CAS  PubMed  Google Scholar 

  66. Gretarsdottir, S. et al. BRCA2 and p53 mutations in primary breast cancer in relation to genetic instability. Cancer Res. 58, 859–862 (1998).

    CAS  PubMed  Google Scholar 

  67. Bertwistle, D. & Ashworth, A. Functions of the BRCA1 and BRCA2 genes. Curr. Opin. Genet. Dev. 8, 14–20 (1998).

    CAS  PubMed  Google Scholar 

  68. 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).

    CAS  PubMed  Google Scholar 

  69. Hashizume, R. et al. The RING heterodimer BRCA1–BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. J. Biol. Chem. 276, 14537–14540 (2001).

    CAS  PubMed  Google Scholar 

  70. Ghimenti, C. et al. Germline mutations of the BRCA1-associated ring domain (BARD1) gene in breast and breast/ovarian families negative for BRCA1 and BRCA2 alterations. Genes Chromosom. Cancer 33, 235–242 (2002).

    CAS  PubMed  Google Scholar 

  71. Ishitobi, M. et al. Mutational analysis of BARD1 in familial breast cancer patients in Japan. Cancer Lett. 200, 1–7 (2003).

    CAS  PubMed  Google Scholar 

  72. Morris, J. R. & Solomon, E. BRCA1: BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair. Hum. Mol. Genet. 13, 807–817 (2004).

    CAS  PubMed  Google Scholar 

  73. Bochar, D. A. et al. BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell 102, 257–265 (2000).

    CAS  PubMed  Google Scholar 

  74. Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998).

    CAS  PubMed  Google Scholar 

  75. Yarden, R. I. & Brody, L. C. BRCA1 interacts with components of the histone deacetylase complex. Proc. Natl Acad. Sci. USA 96, 4983–4988 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 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).

    CAS  PubMed  Google Scholar 

  77. Hughes-Davies, L. et al. EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115, 523–535 (2003).

    CAS  PubMed  Google Scholar 

  78. Tischkowitz, M. D. & Hodgson, S. V. Fanconi anaemia. J. Med. Genet. 40, 1–10 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Howlett, N. G. et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297, 606–609 (2002).

    CAS  PubMed  Google Scholar 

  80. Offit, K. et al. Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J. Natl Cancer Inst. 95, 1548–1551 (2003). References 79 and 80 showed that homozygous truncating mutations in BRCA2 do not necessarily result in embryonic lethality, but do lead to a severe form of childhood cancer. Such an effect has not been seen for BRCA1 mutations

    CAS  PubMed  Google Scholar 

  81. Monteiro, A. N. BRCA1: the enigma of tissue-specific tumor development. Trends Genet. 19, 312–315 (2003).

    CAS  PubMed  Google Scholar 

  82. Elledge, S. J. & Amon, A. The BRCA1 suppressor hypothesis: an explanation for the tissue-specific tumor development in BRCA1 patients. Cancer Cell 1, 129–132 (2002).

    CAS  PubMed  Google Scholar 

  83. Chappuis, P. O., Nethercot, V. & Foulkes, W. D. Clinico-pathological characteristics of BRCA1- and BRCA2-related breast cancer. Semin. Surg. Oncol. 18, 287–295 (2000).

    CAS  PubMed  Google Scholar 

  84. Zeps, N., Bentel, J. M., Papadimitriou, J. M., D'Antuono, M. F. & Dawkins, H. J. Estrogen receptor-negative epithelial cells in mouse mammary gland development and growth. Differentiation 62, 221–226 (1998).

    CAS  PubMed  Google Scholar 

  85. Gompel, A. et al. Hormonal regulation of apoptosis in breast cells and tissues. Steroids 65, 593–598 (2000).

    CAS  PubMed  Google Scholar 

  86. Somai, S. et al. Antiestrogens are pro-apoptotic in normal human breast epithelial cells. Int. J. Cancer 105, 607–612 (2003).

    CAS  PubMed  Google Scholar 

  87. Cameron, D. A., Ritchie, A. A. & Miller, W. R. The relative importance of proliferation and cell death in breast cancer growth and response to tamoxifen. Eur. J. Cancer 37, 1545–1553 (2001).

    CAS  PubMed  Google Scholar 

  88. Antoniou, A. et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am. J. Hum. Genet. 72, 1117–1130 (2003). Provides robust risk estimates and should be required reading for those who counsel women at risk for developing BRCA1 - and BRCA2 -associated cancers.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Adem, C. et al. Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers. Cancer 97, 1–11 (2003).

    PubMed  Google Scholar 

  90. Hoogerbrugge, N. et al. High prevalence of premalignant lesions in prophylactically removed breasts from women at hereditary risk for breast cancer. J. Clin. Oncol. 21, 41–45 (2003).

    CAS  PubMed  Google Scholar 

  91. Kauff, N. D. et al. Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations. Cancer 97, 1601–1608 (2003).

    PubMed  Google Scholar 

  92. Mote, P. A. et al. Germ-line mutations in BRCA1 or BRCA2 in the normal breast are associated with altered expression of estrogen-responsive proteins and the predominance of progesterone receptor A. Genes Chromosom. Cancer 39, 236–248 (2004).

    CAS  PubMed  Google Scholar 

  93. Salazar, H. et al. Microscopic benign and invasive malignant neoplasms and a cancer-prone phenotype in prophylactic oophorectomies. J. Natl Cancer Inst. 88, 1810–1820 (1996).

    CAS  PubMed  Google Scholar 

  94. Stratton, J. F., Buckley, C. H., Lowe, D. & Ponder, B. A. Comparison of prophylactic oophorectomy specimens from carriers and noncarriers of a BRCA1 or BRCA2 gene mutation. United Kingdom Coordinating Committee on Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group. J. Natl Cancer Inst. 91, 626–628 (1999).

    CAS  PubMed  Google Scholar 

  95. Barakat, R. R. et al. Absence of premalignant histologic, molecular, or cell biologic alterations in prophylactic oophorectomy specimens from BRCA1 heterozygotes. Cancer 89, 383–390 (2000).

    CAS  PubMed  Google Scholar 

  96. Skolnick, M. H. et al. Inheritance of proliferative breast disease in breast cancer kindreds. Science 250, 1715–1720 (1990).

    CAS  PubMed  Google Scholar 

  97. Colgan, T. J., Murphy, J., Cole, D. E., Narod, S. & Rosen, B. Occult carcinoma in prophylactic oophorectomy specimens: prevalence and association with BRCA germline mutation status. Am. J. Surg. Pathol. 25, 1283–1289 (2001).

    CAS  PubMed  Google Scholar 

  98. Foray, N. et al. γ-rays-induced death of human cells carrying mutations of BRCA1 or BRCA2. Oncogene 18, 7334–7342 (1999).

    CAS  PubMed  Google Scholar 

  99. Baldeyron, C. et al. A single mutated BRCA1 allele leads to impaired fidelity of double strand break end-joining. Oncogene 21, 1401–1410 (2002).

    CAS  PubMed  Google Scholar 

  100. Coupier, I. et al. Fidelity of DNA double-strand break repair in heterozygous cell lines harbouring BRCA1 missense mutations. Oncogene 23, 914–919 (2004).

    CAS  PubMed  Google Scholar 

  101. Rothfuss, A. et al. Induced micronucleus frequencies in peripheral lymphocytes as a screening test for carriers of a BRCA1 mutation in breast cancer families. Cancer Res. 60, 390–394 (2000).

    CAS  PubMed  Google Scholar 

  102. Baria, K. et al. Correspondence re: A. Rothfuss et al. Induced micronucleus frequencies in peripheral blood lymphocytes as a screening test for carriers of a BRCA1 mutation in breast cancer families. In Cancer Research. 60, 390–394, 2000. Cancer Res. 61, 5948–5949 (2001).

    Google Scholar 

  103. Cornelis, R. S. et al. High allele loss rates at 17q12–q21 in breast and ovarian tumors from BRCA1-linked families. The Breast Cancer Linkage Consortium. Genes Chromosom. Cancer 13, 203–210 (1995).

    CAS  PubMed  Google Scholar 

  104. Smith, S. A., Easton, D. F., Evans, D. G. & Ponder, B. A. Allele losses in the region 17q12–21 in familial breast and ovarian cancer involve the wild-type chromosome. Nature Genet. 2, 128–131 (1992).

    CAS  PubMed  Google Scholar 

  105. Futreal, P. A. et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science 266, 120–122 (1994).

    CAS  PubMed  Google Scholar 

  106. Sorlie, T., Andersen, T. I., Bukholm, I. & Borresen-Dale, A. L. Mutation screening of BRCA1 using PTT and LOH analysis at 17q21 in breast carcinomas from familial and non-familial cases. Breast Cancer Res. Treat. 48, 259–264 (1998).

    CAS  PubMed  Google Scholar 

  107. Merajver, S. D. et al. Somatic mutations in the BRCA1 gene in sporadic ovarian tumours. Nature Genet. 9, 439–443 (1995).

    CAS  PubMed  Google Scholar 

  108. Hosking, L. et al. A somatic BRCA1 mutation in an ovarian tumour. Nature Genet. 9, 343–344 (1995).

    CAS  PubMed  Google Scholar 

  109. Haber, D. Roads leading to breast cancer. N. Engl. J. Med. 343, 1566–1568 (2000).

    CAS  PubMed  Google Scholar 

  110. Narod, S. Roads to breast cancer. N. Engl. J. Med. 344, 937 (2001).

    CAS  PubMed  Google Scholar 

  111. Foulkes, W. D. BRCA1 functions as a breast stem cell regulator. J. Med. Genet. 41, 1–5 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Greenblatt, M. S., Bennett, W. P., Hollstein, M. & Harris, C. C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 54, 4855–4878 (1994).

    CAS  PubMed  Google Scholar 

  113. Magdinier, F. et al. Regional methylation of the 5′ end CpG island of BRCA1 is associated with reduced gene expression in human somatic cells. FASEB J. 14, 1585–1594 (2000).

    CAS  PubMed  Google Scholar 

  114. Catteau, A., Harris, W. H., Xu, C. F. & Solomon, E. Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer: correlation with disease characteristics. Oncogene 18, 1957–1965 (1999).

    CAS  PubMed  Google Scholar 

  115. Esteller, M. et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J. Natl Cancer Inst. 92, 564–569 (2000).

    CAS  PubMed  Google Scholar 

  116. Thompson, M. E., Jensen, R. A., Obermiller, P. S., Page, D. L. & Holt, J. T. Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nature Genet. 9, 444–450 (1995).

    CAS  PubMed  Google Scholar 

  117. Magdinier, F., Ribieras, S., Lenoir, G. M., Frappart, L. & Dante, R. Down-regulation of BRCA1 in human sporadic breast cancer; analysis of DNA methylation patterns of the putative promoter region. Oncogene 17, 3169–3176 (1998).

    CAS  PubMed  Google Scholar 

  118. Seery, L. T. et al. BRCA1 expression levels predict distant metastasis of sporadic breast cancers. Int. J. Cancer 84, 258–262 (1999).

    CAS  PubMed  Google Scholar 

  119. Lambie, H. et al. Prognostic significance of BRCA1 expression in sporadic breast carcinomas. J. Pathol. 200, 207–213 (2003).

    CAS  PubMed  Google Scholar 

  120. Lakhani, S. R. et al. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J. Natl Cancer Inst. 90, 1138–1145 (1998).

    CAS  PubMed  Google Scholar 

  121. Jacquemier, J., Lidereau, R., Birnbaum, D., Eisinger, F. & Sobol, H. Assessing the risk of BRCA1-associated breast cancer using individual morphological criteria. Histopathol. 38, 378–379 (2001).

    CAS  Google Scholar 

  122. Quenneville, L. A. et al. HER-2/neu status and tumor morphology of invasive breast carcinomas in Ashkenazi women with known BRCA1 mutation status in the Ontario Familial Breast Cancer Registry. Cancer 95, 2068–2075 (2002).

    CAS  PubMed  Google Scholar 

  123. Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    CAS  PubMed  Google Scholar 

  124. Van't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    CAS  Google Scholar 

  125. Gruvberger, S. et al. Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns. Cancer Res. 61, 5979–5984 (2001).

    CAS  PubMed  Google Scholar 

  126. Sorlie, T. et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc. Natl Acad. Sci. USA 100, 8418–8423 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Foulkes, W. D. et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J. Natl Cancer Inst. 95, 1482–1485 (2003).

    CAS  PubMed  Google Scholar 

  128. Korsching, E. et al. Cytogenetic alterations and cytokeratin expression patterns in breast cancer: integrating a new model of breast differentiation into cytogenetic pathways of breast carcinogenesis. Lab. Invest. 82, 1525–1533 (2002).

    CAS  PubMed  Google Scholar 

  129. Bocker, W. et al. Common adult stem cells in the human breast give rise to glandular and myoepithelial cell lineages: a new cell biological concept. Lab. Invest. 82, 737–745 (2002). References 126–129 report the existence of a basal subtype of breast cancer, and references 126 and 127 show that this tumour phenotype is over-represented in carriers of BRCA1 mutations compared with other types of breast cancer.

    PubMed  Google Scholar 

  130. Robson, M. E., Boyd, J., Borgen, P. I. & Cody, H. S. Hereditary breast cancer. Curr. Probl. Surg. 38, 387–480 (2001).

    CAS  PubMed  Google Scholar 

  131. Evans, D. G. & Howell, A. Are BRCA1- and BRCA2–related breast cancers associated with increased mortality? Breast Cancer Res. 6, E7 (2004).

    PubMed  Google Scholar 

  132. Robson, M. E. et al. A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment. Breast Cancer Res. 6, R8–R17 (2004).

    CAS  PubMed  Google Scholar 

  133. Quinn, J. E. et al. BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. Cancer Res. 63, 6221–6228 (2003).

    CAS  PubMed  Google Scholar 

  134. Chappuis, P. O. et al. A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer. J. Med. Genet. 39, 608–610 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Foulkes, W. D. et al. Disruption of the expected positive correlation between breast tumor size and lymph node status in BRCA1-related breast carcinoma. Cancer 98, 1569–1577 (2003).

    PubMed  Google Scholar 

  136. Goffin, J. R. et al. Impact of germline BRCA1 mutations and overexpression of p53 on prognosis and response to treatment following breast carcinoma: 10-year follow up data. Cancer 97, 527–536 (2003).

    CAS  PubMed  Google Scholar 

  137. Moller, P. et al. Survival in prospectively ascertained familial breast cancer: analysis of a series stratified by tumour characteristics, BRCA mutations and oophorectomy. Int. J. Cancer 101, 555–559 (2002).

    CAS  PubMed  Google Scholar 

  138. Eerola, H. et al. Survival of breast cancer patients in BRCA1, BRCA2, and non-BRCA1/2 breast cancer families: a relative survival analysis from Finland. Int. J. Cancer 93, 368–372 (2001).

    CAS  PubMed  Google Scholar 

  139. Metcalfe, K. et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J. Clin. Oncol. 22, 2328–2335 (2004).

    CAS  PubMed  Google Scholar 

  140. Narod, S. A. et al. Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Hereditary Breast Cancer Clinical Study Group. Lancet 356, 1876–1881 (2000).

    CAS  PubMed  Google Scholar 

  141. Hedenfalk, I. et al. Gene-expression profiles in hereditary breast cancer. N. Engl. J. Med. 344, 539–548 (2001).

    CAS  PubMed  Google Scholar 

  142. Moslehi, R. et al. BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am. J. Hum. Genet. 66, 1259–1272 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Boyd, J. et al. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA 283, 2260–2265 (2000).

    CAS  PubMed  Google Scholar 

  144. Gotlieb, W. H. et al. Rates of Jewish ancestral mutations in BRCA1 and BRCA2 in borderline ovarian tumors. J. Natl Cancer Inst. 90, 995–1000 (1998).

    CAS  PubMed  Google Scholar 

  145. Jazaeri, A. A. et al. Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers. J. Natl Cancer Inst. 94, 990–1000 (2002).

    CAS  PubMed  Google Scholar 

  146. Peto, J. Breast cancer susceptibility — a new look at an old model. Cancer Cell 1, 411–412 (2002).

    CAS  PubMed  Google Scholar 

  147. Sobol, H., Birnbaum, D. & Eisinger, F. Evidence for a third breast-cancer susceptibility gene. Lancet 344, 1151–1152 (1994).

    CAS  PubMed  Google Scholar 

  148. Seitz, S. et al. Strong indication for a breast cancer susceptibility gene on chromosome 8p12–p22: linkage analysis in German breast cancer families. Oncogene 14, 741–743 (1997).

    CAS  PubMed  Google Scholar 

  149. Kainu, T. et al. Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus. Proc. Natl Acad. Sci. USA 97, 9603–9608 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Rahman, N. et al. Absence of evidence for a familial breast cancer susceptibility gene at chromosome 8p12–p22. Oncogene 19, 4170–4173 (2000).

    CAS  PubMed  Google Scholar 

  151. Thompson, D. et al. Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium. Proc. Natl Acad. Sci. USA 99, 827–831 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Cui, J. et al. After BRCA1 and BRCA2 — what next? Multifactorial segregation analyses of three-generation, population-based Australian families affected by female breast cancer. Am. J. Hum. Genet. 68, 420–431 (2001).

    CAS  PubMed  Google Scholar 

  153. Liede, A. et al. Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan. Am. J. Hum. Genet. 71, 595–606 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Lakhani, S. R. et al. The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2. Clin. Cancer Res. 6, 782–789 (2000).

    CAS  PubMed  Google Scholar 

  155. Hedenfalk, I. et al. Molecular classification of familial non-BRCA1/BRCA2 breast cancer. Proc. Natl Acad. Sci. USA 100, 2532–2537 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Pharoah, P. D. et al. Polygenic susceptibility to breast cancer and implications for prevention. Nature Genet. 31, 33–36 (2002). Looks towards the future of breast cancer genetics — there is probably no single BRCA3 gene, but rather many low-penetrance, low-frequency genes are likely to underlie the remaining cases of familial breast cancer.

    CAS  PubMed  Google Scholar 

  157. Swift, M. & Chase, C. Cancer and cardiac deaths in obligatory ataxia-telangiectasia heterozygotes. Lancet 1, 1049–1050 (1983).

    CAS  PubMed  Google Scholar 

  158. Easton, D. F. Cancer risks in A-T heterozygotes. Int. J. Radiat. Biol. 66, S177–S182 (1994).

    CAS  PubMed  Google Scholar 

  159. Chenevix-Trench, G. et al. Dominant negative ATM mutations in breast cancer families. J. Natl Cancer Inst. 94, 205–215 (2002).

    PubMed  Google Scholar 

  160. Fitzgerald, M. G. et al. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nature Genet. 15, 307–310 (1997).

    CAS  PubMed  Google Scholar 

  161. Scott, S. P. et al. Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. Proc. Natl Acad. Sci. USA 99, 925–930 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Gatti, R. A., Tward, A. & Concannon, P. Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol. Genet. Metab. 68, 419–423 (1999).

    CAS  PubMed  Google Scholar 

  163. Stankovic, T. et al. ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am. J. Hum. Genet. 62, 334–345 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Szabo, C. I. et al. Are ATM mutations 7271T>G and IVS10-6T>G really high-risk breast cancer-susceptibility alleles? Cancer Res. 64, 840–843 (2004).

    CAS  PubMed  Google Scholar 

  165. Wu, X., Webster, S. R. & Chen, J. Characterization of tumor-associated Chk2 mutations. J. Biol. Chem. 276, 2971–2974 (2001).

    CAS  PubMed  Google Scholar 

  166. Meijers-Heijboer, H. et al. Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nature Genet. 31, 55–59 (2002).

    CAS  PubMed  Google Scholar 

  167. Oldenburg, R. A. et al. The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. Cancer Res. 63, 8153–8157 (2003).

    CAS  PubMed  Google Scholar 

  168. Vahteristo, P. et al. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am. J. Hum. Genet. 71, 432–438 (2002). References 166–168 describe the relation between CHK2 and familial breast cancer and provide important examples of how breast cancer predisposition is likely to be caused by polygenic factors.

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Offit, K. et al. Frequency of CHEK2*1100delC in New York breast cancer cases and controls. BMC Med. Genet. 4, 1 (2003).

    PubMed  PubMed Central  Google Scholar 

  170. Matsuoka, S. et al. Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc. Natl Acad. Sci. USA 97, 10389–10394 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Chaturvedi, P. et al. Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene 18, 4047–4054 (1999).

    CAS  PubMed  Google Scholar 

  172. Ahn, J. Y., Schwarz, J. K., Piwnica-Worms, H. & Canman, C. E. Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation. Cancer Res. 60, 5934–5936 (2000).

    CAS  PubMed  Google Scholar 

  173. Falck, J., Mailand, N., Syljuasen, R. G., Bartek, J. & Lukas, J. The ATM–Chk2–Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410, 842–847 (2001).

    CAS  PubMed  Google Scholar 

  174. Chehab, N. H., Malikzay, A., Appel, M. & Halazonetis, T. D. Chk2/hCds1 functions as a DNA damage checkpoint in G1 by stabilizing p53. Genes Dev. 14, 278–288 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Shieh, S. Y., Ahn, J., Tamai, K., Taya, Y. & Prives, C. The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev. 14, 289–300 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Lee, J. S., Collins, K. M., Brown, A. L., Lee, C. H. & Chung, J. H. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404, 201–204 (2000).

    CAS  PubMed  Google Scholar 

  177. Bell, D. W. et al. Heterozygous germ line hCHK2 mutations in Li–Fraumeni syndrome. Science 286, 2528–2531 (1999).

    CAS  PubMed  Google Scholar 

  178. Jasin, M. Homologous repair of DNA damage and tumorigenesis: the BRCA connection. Oncogene 21, 8981–8993 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Work in W.D.F.'s laboratory is funded by the US Army, the Susan G. Komen Breast Cancer Foundation and the Canadian Breast Cancer Alliance.

Author information

Authors and Affiliations

  1. Centre for Research on Women's Health, Sunnybrook and Womens College Health Sciences Center, 790 Bay Street, Toronto, M5G 1N8, Ontario, Canada

    Steven A. Narod

  2. Departments of Oncology and Human Genetics, Program in Cancer Genetics, McGill University, Montreal, H3G 1A4, Quebec, Canada

    William D. Foulkes

Authors
  1. Steven A. Narod
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William D. Foulkes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven A. Narod.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Cancer.gov

breast cancer

endometrial cancer

ovarian cancer

prostate cancer

Wilms' tumour

Entrez Gene

ATM

BARD1

BRCA1

BRCA2

CHK2

cyclin D1

cyclin E

EMSY

ER

ERBB2

KIP1

p53

RAD51

WAF1

OMIM

Fanconi anaemia

FURTHER INFORMATION

The Breast Cancer Information Core

The Breast Cancer Linkage Consortium

Glossary

MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION

A technique used to determine the copy number of multiple specific sequences in a single reaction. Two probes are hybridized to the target sequence and are joined together by ligation to make a copy of that sequence. The probes are designed so that all the products can be amplified using the same primer pair. The relative quantity of each product establishes the copy number of the target sequence.

A LU SEQUENCES

Short interspersed nuclear elements present at a high frequency in primate genomes. Alu sequences are amplified in the genome by retrotransposition. A complete Alu sequence is approximately 300 bp long and contains an A-rich region near the centre and a stretch of As at the 3′ end.

FOUNDER MUTATIONS

Specific mutations that appear repeatedly in ethnically defined groups because of a shared common ancestry and, typically, rapid population growth.

RAD51 FOCI

Discrete nuclear foci comprised of DNA-repair complexes that accumulate after endogenous or induced DNA damage. BRCA2 is a component of these foci and delivers RAD51 to the sites of DNA damage. BRCA1 might also be required to complete these foci.

PROTEASOME

An organelle that breaks down proteins that have been targeted for degradation by ubiquitylation (by having a ubiquitin tag added to the protein). Lack of regulation of proteasomal degradation leads, for example, to loss of control of the cell cycle and seems to be an important step in tumorigenesis.

RING-FINGER MOTIF

A motif comprised of cysteine and histidine residues interspaced with hydrophobic amino acids. Proteins that contain this motif usually have ubiquitin-ligase functions.

TWO-HIT MODEL OF TUMORIGENESIS

States that both alleles of a tumour-suppressor gene need to be inactivated to promote unregulated tumour-cell growth. A given allele could be inactivated due to inherited mutation (constitutional), somatic mutation or epigenetic silencing. Hereditary tumours would be caused by an inherited mutation and a somatic mutation; non-hereditary tumours would be the result of two somatic mutations.

BASAL PHENOTYPE

Describes a relatively rare subtype of breast cancer that can be defined by immunohistochemistry. These tumours express markers that are typically seen in normal basal breast and skin epithelium, such as cytokeratins 5 and 6. This phenotype is often associated with a poor outcome.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Narod, S., Foulkes, W. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 4, 665–676 (2004). https://doi.org/10.1038/nrc1431

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1431

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing