Human Molecular Genetics, 2001, Vol. 10, No. 7 705-713
© 2001 Oxford University Press
BRCA1 and BRCA2 and the genetics of breast and ovarian cancer
Departments of Medicine and Genetics, Box 357720, University of Washington, Seattle, WA 98195-7720, USA
Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose individuals to breast and ovarian cancers. Progress in determining the function of BRCA1 and BRCA2 suggests that they are involved in two fundamental cellular processes: DNA damage repair and transcriptional regulation. We evaluate current knowledge of BRCA1 and BRCA2 functions to explain why mutations in BRCA1 and BRCA2 lead specifically to breast and ovarian cancer. The BRCA1 and BRCA2 genes contain unusually high densities of repetitive elements. These features of the BRCAs genomic regions contribute to chromosomal instability of these genes. We propose that somatic alterations of BRCA1 and BRCA2 are common and driven by rearrangements between repetitive elements. Inherited and somatic mutations occur in BRCA1 and BRCA2; virtually all somatic mutations are the result of large genomic rearrangements. What are the consequences of such large somatic mutations of BRCA1 and BRCA2 in women with or without inherited mutations? The breast and ovary are estrogen-responsive tissues. Beginning in puberty, the breast epithelium proliferates rapidly in response to fluctuating levels of estrogen. We present a genetic model outlining how BRCA-deficient cells may gain uncontrolled proliferation leading to tumor formation. Central to this model of BRCA-mediated tumorigenesis are estrogen-mediated proliferation of breast and ovarian epithelium and the distinctive genomic context of the BRCA genes.
+ To whom correspondence should be addressed. Tel: +1 206 616 4294; Fax: +1 206 616 4295; Email: piri@u.washington.edu
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. Pasanisi, G. Hedelin, J. Berrino, J. Chang-Claude, S. Hermann, M. Steel, N. Haites, J. Hart, R. Peled, L. Gafa, et al. Oral Contraceptive Use and BRCA Penetrance: A Case-Only Study Cancer Epidemiol. Biomarkers Prev., July 1, 2009; 18(7): 2107 - 2113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.-F. Richard, A. Kerrest, and B. Dujon Comparative Genomics and Molecular Dynamics of DNA Repeats in Eukaryotes Microbiol. Mol. Biol. Rev., December 1, 2008; 72(4): 686 - 727. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Marini, A. Bitto, D. Altavilla, B. P. Burnett, F. Polito, V. Di Stefano, L. Minutoli, M. Atteritano, R. M. Levy, R. D'Anna, et al. Breast Safety and Efficacy of Genistein Aglycone for Postmenopausal Bone Loss: A Follow-Up Study J. Clin. Endocrinol. Metab., December 1, 2008; 93(12): 4787 - 4796. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. S. Walsh, S. Ogawa, D. R. Scoles, C. W. Miller, N. Kawamata, S. A. Narod, H. P. Koeffler, and B. Y. Karlan Genome-Wide Loss of Heterozygosity and Uniparental Disomy in BRCA1/2-Associated Ovarian Carcinomas Clin. Cancer Res., December 1, 2008; 14(23): 7645 - 7651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Altshuler, M. J. Daly, and E. S. Lander Genetic Mapping in Human Disease Science, November 7, 2008; 322(5903): 881 - 888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-D. Lee, S.-C. Chen, C. H. Chan, C.-H. Lu, C.-C. Chen, J.-T. Lin, M.-F. Chen, S.-H. Huang, C.-M. Yeh, and M.-C. Chen Increased Risk for Second Primary Malignancies in Women with Breast Cancer Diagnosed at Young Age: A Population-Based Study in Taiwan Cancer Epidemiol. Biomarkers Prev., October 1, 2008; 17(10): 2647 - 2655. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. I. Weberpals, K. V. Clark-Knowles, and B. C. Vanderhyden Sporadic Epithelial Ovarian Cancer: Clinical Relevance of BRCA1 Inhibition in the DNA Damage and Repair Pathway J. Clin. Oncol., July 1, 2008; 26(19): 3259 - 3267. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Park, Y.-J. Seok, G. Jeong, and J.-S. Lee SUMO1 negatively regulates BRCA1-mediated transcription, via modulation of promoter occupancy Nucleic Acids Res., January 17, 2008; 36(1): 263 - 283. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. H. Vaz, P. M. Machado, R. D. Brandao, C. T. Laranjeira, J. S. Eugenio, A. H. Fernandes, and S. P. Andre Familial Breast/Ovarian Cancer and BRCA1/2 Genetic Screening: The Role of Immunohistochemistry as an Additional Method in the Selection of Patients J. Histochem. Cytochem., November 1, 2007; 55(11): 1105 - 1113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Paz, E. Y. Levanon, N. Amariglio, A. B. Heimberger, Z. Ram, S. Constantini, Z. S. Barbash, K. Adamsky, M. Safran, A. Hirschberg, et al. Altered adenosine-to-inosine RNA editing in human cancer Genome Res., November 1, 2007; 17(11): 1586 - 1595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Machado, R. D. Brandao, B. M. Cavaco, J. Eugenio, S. Bento, M. Nave, P. Rodrigues, A. Fernandes, and F. Vaz Screening for a BRCA2 Rearrangement in High-Risk Breast/Ovarian Cancer Families: Evidence for a Founder Effect and Analysis of the Associated Phenotypes J. Clin. Oncol., May 20, 2007; 25(15): 2027 - 2034. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Eakin, M. J. MacCoss, G. L. Finney, and R. E. Klevit Estrogen receptor {alpha} is a putative substrate for the BRCA1 ubiquitin ligase PNAS, April 3, 2007; 104(14): 5794 - 5799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. DelloRusso, P. L. Welcsh, W. Wang, R. L. Garcia, M.-C. King, and E. M. Swisher Functional Characterization of a Novel BRCA1-Null Ovarian Cancer Cell Line in Response to Ionizing Radiation Mol. Cancer Res., January 1, 2007; 5(1): 35 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Pageau and J. B. Lawrence BRCA1 foci in normal S-phase nuclei are linked to interphase centromeres and replication of pericentric heterochromatin J. Cell Biol., December 4, 2006; 175(5): 693 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Harris, M. Lowden, I. Clejan, M. Tzoneva, J. H. Thomas, J. Hodgkin, and S. Ahmed Mutator Phenotype of Caenorhabditis elegans DNA Damage Checkpoint Mutants Genetics, October 1, 2006; 174(2): 601 - 616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Cousineau, C. Abaji, and A. Belmaaza BRCA1 Regulates RAD51 Function in Response to DNA Damage and Suppresses Spontaneous Sister Chromatid Replication Slippage: Implications for Sister Chromatid Cohesion, Genome Stability, and Carcinogenesis Cancer Res., December 15, 2005; 65(24): 11384 - 11391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Agata, M Dalla Palma, M Callegaro, M C Scaini, C Menin, C Ghiotto, O Nicoletto, G Zavagno, L Chieco-Bianchi, E D'Andrea, et al. Large genomic deletions inactivate the BRCA2 gene in breast cancer families J. Med. Genet., October 1, 2005; 42(10): e64 - e64. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Gonzalez-Zuloeta Ladd, A. Arias Vasquez, F. A. Sayed-Tabatabaei, J.W. Coebergh, A. Hofman, O. Njajou, B. Stricker, and C. van Duijn Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism and Breast Cancer Risk Cancer Epidemiol. Biomarkers Prev., September 1, 2005; 14(9): 2143 - 2146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A M Woodward, T A Davis, A G S Silva, kConFab Investigators, J A Kirk, and J A Leary Large genomic rearrangements of both BRCA2 and BRCA1 are a feature of the inherited breast/ovarian cancer phenotype in selected families J. Med. Genet., May 1, 2005; 42(5): e31 - e31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Pavlicek, V. N. Noskov, N. Kouprina, J. C. Barrett, J. Jurka, and V. Larionov Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition Hum. Mol. Genet., November 15, 2004; 13(22): 2737 - 2751. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Yu and J. Chen DNA Damage-Induced Cell Cycle Checkpoint Control Requires CtIP, a Phosphorylation-Dependent Binding Partner of BRCA1 C-Terminal Domains Mol. Cell. Biol., November 1, 2004; 24(21): 9478 - 9486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Parrella, M. L. Poeta, A. P. Gallo, M. Prencipe, M. Scintu, A. Apicella, R. Rossiello, G. Liguoro, D. Seripa, C. Gravina, et al. Nonrandom Distribution of Aberrant Promoter Methylation of Cancer-Related Genes in Sporadic Breast Tumors Clin. Cancer Res., August 15, 2004; 10(16): 5349 - 5354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Beger, M. Ramadani, S. Meyer, G. Leder, M. Kruger, K. Welte, F. Gansauge, and H. G. Beger Down-Regulation of BRCA1 in Chronic Pancreatitis and Sporadic Pancreatic Adenocarcinoma Clin. Cancer Res., June 1, 2004; 10(11): 3780 - 3787. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Tan, L. Zheng, W.-H. Lee, and T. G. Boyer Functional Dissection of Transcription Factor ZBRK1 Reveals Zinc Fingers with Dual Roles in DNA-binding and BRCA1-dependent Transcriptional Repression J. Biol. Chem., February 20, 2004; 279(8): 6576 - 6587. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Nishikawa, S. Ooka, K. Sato, K. Arima, J. Okamoto, R. E. Klevit, M. Fukuda, and T. Ohta Mass Spectrometric and Mutational Analyses Reveal Lys-6-linked Polyubiquitin Chains Catalyzed by BRCA1-BARD1 Ubiquitin Ligase J. Biol. Chem., February 6, 2004; 279(6): 3916 - 3924. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. C. Wang, M. Lin, L.-J. Wei, C. Li, A. Miron, G. Lodeiro, L. Harris, S. Ramaswamy, D. M. Tanenbaum, M. Meyerson, et al. Loss of Heterozygosity and Its Correlation with Expression Profiles in Subclasses of Invasive Breast Cancers Cancer Res., January 1, 2004; 64(1): 64 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Staff, J. Isola, and M. Tanner Haplo-insufficiency of BRCA1 in Sporadic Breast Cancer Cancer Res., August 15, 2003; 63(16): 4978 - 4983. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T I Orban and E Olah Emerging roles of BRCA1 alternative splicing Mol. Pathol., August 1, 2003; 56(4): 191 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T Ikonen, M P Matikainen, K Syrjakoski, N Mononen, P A Koivisto, A Rokman, E H Seppala, O-P Kallioniemi, T L J Tammela, and J Schleutker BRCA1 and BRCA2 mutations have no major role in predisposition to prostate cancer in Finland J. Med. Genet., August 1, 2003; 40(8): e98 - 98. [Full Text] [PDF]
|
|
|
|
|
|
E. E. McCarthy, J. T. Celebi, R. Baer, and T. Ludwig Loss of Bard1, the Heterodimeric Partner of the Brca1 Tumor Suppressor, Results in Early Embryonic Lethality and Chromosomal Instability Mol. Cell. Biol., July 15, 2003; 23(14): 5056 - 5063. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Kim, K. C. Park, S. S. Chung, O. Bang, and C. H. Chung Deubiquitinating Enzymes as Cellular Regulators J. Biochem., July 1, 2003; 134(1): 9 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. R. Thorstenson, A. Roxas, R. Kroiss, M. A. Jenkins, K. M. Yu, T. Bachrich, D. Muhr, T. L. Wayne, G. Chu, R. W. Davis, et al. Contributions of ATM Mutations to Familial Breast and Ovarian Cancer Cancer Res., June 15, 2003; 63(12): 3325 - 3333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. Brzovic, J. R. Keeffe, H. Nishikawa, K. Miyamoto, D. Fox III, M. Fukuda, T. Ohta, and R. Klevit Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex PNAS, May 13, 2003; 100(10): 5646 - 5651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. Nexo, U. Vogel, A. Olsen, T. Ketelsen, Z. Bukowy, B. L. Thomsen, H. Wallin, K. Overvad, and A. Tjonneland A specific haplotype of single nucleotide polymorphisms on chromosome 19q13.2-3 encompassing the gene RAI is indicative of post-menopausal breast cancer before age 55 Carcinogenesis, May 1, 2003; 24(5): 899 - 904. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Fleming, J. D. Potter, C. J. Ramirez, G. K. Ostrander, and E. A. Ostrander Understanding missense mutations in the BRCA1 gene: An evolutionary approach PNAS, February 4, 2003; 100(3): 1151 - 1156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Liu, D. M. Virshup, R. L. White, and L.-C. Hsu Regulation of BRCA1 Phosphorylation by Interaction with Protein Phosphatase 1{alpha} Cancer Res., November 15, 2002; 62(22): 6357 - 6361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S Gad, M Klinger, V Caux-Moncoutier, S Pages-Berhouet, M Gauthier-Villars, I Coupier, A Bensimon, A Aurias, and D Stoppa-Lyonnet Bar code screening on combed DNA for large rearrangements of the BRCA1 and BRCA2 genes in French breast cancer families J. Med. Genet., November 1, 2002; 39(11): 817 - 821. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Bertucci, F. Eisinger, R. Tagett, H. Sobol, and D. Birnbaum Re: Gene Expression Profiles of BRCA1-Linked, BRCA2-Linked, and Sporadic Ovarian Cancers J Natl Cancer Inst, October 2, 2002; 94(19): 1506 - 1507. [Full Text] [PDF]
|
|
|
|
|
|
C. M. Wong, J. M. F. Lee, T. C. M. Lau, S. T. Fan, and I. O. L. Ng Clinicopathological Significance of Loss of Heterozygosity on Chromosome 13q in Hepatocellular Carcinoma Clin. Cancer Res., July 1, 2002; 8(7): 2266 - 2272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Chenevix-Trench, T. Dork, C. Scott, and J. Hopper RESPONSE: Re: Dominant Negative ATM Mutations in Breast Cancer Families J Natl Cancer Inst, June 19, 2002; 94(12): 952 - 952. [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-F. Hu and R. Li JunB potentiates function of BRCA1 activation domain 1 (AD1) through a coiled-coil-mediated interaction Genes & Dev., June 15, 2002; 16(12): 1509 - 1517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Gu, R. Y. Lee, T. C. Skaar, K. B. Bouker, J. N. Welch, J. Lu, A. Liu, Y. Zhu, N. Davis, F. Leonessa, et al. Association of Interferon Regulatory Factor-1, Nucleophosmin, Nuclear Factor-{kappa}B, and Cyclic AMP Response Element Binding with Acquired Resistance to Faslodex (ICI 182,780) Cancer Res., June 1, 2002; 62(12): 3428 - 3437. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Sobczak and W. J. Krzyzosiak Structural Determinants of BRCA1 Translational Regulation J. Biol. Chem., May 3, 2002; 277(19): 17349 - 17358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Thompson and D. Easton Variation in BRCA1 Cancer Risks by Mutation Position Cancer Epidemiol. Biomarkers Prev., April 1, 2002; 11(4): 329 - 336. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Hu, G. Li, W.-J. Li, C. Wang, A. M. Goldstein, Z.-Z. Tang, M. J. Roth, S. M. Dawsey, J. Huang, Q.-H. Wang, et al. Infrequent Mutation in the BRCA2 Gene in Esophageal Squamous Cell Carcinoma Clin. Cancer Res., April 1, 2002; 8(4): 1121 - 1126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-C. King, S. Wieand, K. Hale, M. Lee, T. Walsh, K. Owens, J. Tait, L. Ford, B. K. Dunn, J. Costantino, et al. Tamoxifen and Breast Cancer Incidence Among Women With Inherited Mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial JAMA, November 14, 2001; 286(18): 2251 - 2256. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Hanks Genetic Technologies and Women: The Importance of Context Inmaculada de Melo-Martin St. Mary's University Bulletin of Science Technology Society, October 1, 2001; 21(5): 354 - 360. [Abstract] [PDF]
|
|