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Gene Review

Brca1  -  breast cancer 1

Mus musculus

Synonyms: Breast cancer type 1 susceptibility protein homolog
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Disease relevance of Brca1

  • Furthermore, inactivation of Chk2 and Brca1 was cooperative in breast cancer [1].
  • Uterus hyperplasia and increased carcinogen-induced tumorigenesis in mice carrying a targeted mutation of the Chk2 phosphorylation site in Brca1 [2].
  • We developed genetically defined primary mouse ovarian surface epithelial (OSE) cell lines in which the loss of functional Brca1 and p53 recapitulates the events that are thought to occur in early ovarian cancer development in patients with Brca1 mutations [3].
  • Hypersensitivity of Brca1-deficient MEF to the DNA interstrand crosslinking agent mitomycin C is associated with defect in homologous recombination repair and aberrant S-phase arrest [4].
  • Furthermore, haploid loss of ATM also rescued Brca1 deficiency-associated embryonic lethality and premature aging [5].

High impact information on Brca1

  • These findings impact on the interpretation of the relationship between synaptic errors and sterility in mammals and extend our understanding of the biology of Brca1 [6].
  • Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis [7].
  • We have previously reported a mouse model in which Brca1 exon 11 is eliminated in mammary epithelial cells through Cre-mediated excision [7].
  • Cre-mediated excision of exon 11 of the breast-tumour suppressor gene Brca1 in mouse mammary epithelial cells causes increased apoptosis and abnormal ductal development [8].
  • 5. The development of most Brca1 (5-6): p21 double-mutant embryos was comparable to that of their wild-type littermates, although no mutant survived past E10 [9].

Chemical compound and disease context of Brca1


Biological context of Brca1


Anatomical context of Brca1

  • Thus, the outcome of Brca1 deficiency was dependent on cellular context, with the major defects being increased apoptosis in thymocytes, and defective proliferation in peripheral T cells [17].
  • The Brca1 wild-type and Brca1-deficient mouse ovarian tumors and cell lines provide a new experimental system for the evaluation of therapies that target the Brca1 pathway [3].
  • The transformed Brca1-deficient OSE cells display an increased number of centrosomes, acquire complex chromosome aberrations, and lack Rad51 nuclear foci in the presence of DNA-damaging agents, such as mitomycin C and cisplatin [3].
  • Male Brca1(Delta11/Delta11)p53(+/-) mice that carried a homozygous deletion of Brca1 exon 11 and a p53 heterozygous mutation had significantly reduced testicular size and no spermatozoa in their seminiferous tubules [18].
  • Brca1 and Brca2 are expressed concordantly in proliferating cells of embryos, and the mammary gland undergoing morphogenesis and in most adult tissues [19].

Associations of Brca1 with chemical compounds

  • Effects of Novel Retinoic Acid Metabolism Blocking Agent (VN/14-1) on Letrozole-Insensitive Breast Cancer Cells [20].
  • Mouse mammary tumorigenesis is greatly influenced by a variety of exogenous agents, such as MMTV, chemical carcinogens (i.e., polycyclic aromatic hydrocarbons), and radiation, as well as by endogenous/physiological factors, such as steroid hormones, tumor-suppressor genes (i.e., Brca1/2, p53), and gene products of modifier genes [21].
  • The increased growth inhibition to doxorubicin after loss of Brca1 correlated with increased cell killing caused by increased apoptosis [22].
  • Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist [23].
  • We used mice with a Brca1 mutation on a BALB/cJ inbred background (BALB/cB1+/- mice) or a Brca2 genetic alteration on the 129/SvEv genetic background (129B2+/- mice) to investigate potential gene-environment interactions between defects in these genes and treatment with the highly estrogenic compound diethylstilbestrol (DES) [24].

Physical interactions of Brca1

  • These experiments extend our knowledge of a complex Brca1/Trp53 relationship [25].

Enzymatic interactions of Brca1

  • Third, Brca1(-/-) MEFs exhibited a 50-100-fold deficiency in microhomology-mediated end-joining activity of a defined chromosomal DNA double strand break introduced by a rare cutting endonuclease I-SceI [26].

Regulatory relationships of Brca1


Other interactions of Brca1


Analytical, diagnostic and therapeutic context of Brca1


  1. Collaboration of Brca1 and Chk2 in tumorigenesis. McPherson, J.P., Lemmers, B., Hirao, A., Hakem, A., Abraham, J., Migon, E., Matysiak-Zablocki, E., Tamblyn, L., Sanchez-Sweatman, O., Khokha, R., Squire, J., Hande, M.P., Mak, T.W., Hakem, R. Genes Dev. (2004) [Pubmed]
  2. Uterus hyperplasia and increased carcinogen-induced tumorigenesis in mice carrying a targeted mutation of the Chk2 phosphorylation site in Brca1. Kim, S.S., Cao, L., Li, C., Xu, X., Huber, L.J., Chodosh, L.A., Deng, C.X. Mol. Cell. Biol. (2004) [Pubmed]
  3. A mouse model for the molecular characterization of brca1-associated ovarian carcinoma. Xing, D., Orsulic, S. Cancer Res. (2006) [Pubmed]
  4. Hypersensitivity of Brca1-deficient MEF to the DNA interstrand crosslinking agent mitomycin C is associated with defect in homologous recombination repair and aberrant S-phase arrest. Yun, J., Zhong, Q., Kwak, J.Y., Lee, W.H. Oncogene (2005) [Pubmed]
  5. ATM-Chk2-p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency. Cao, L., Kim, S., Xiao, C., Wang, R.H., Coumoul, X., Wang, X., Li, W.M., Xu, X.L., De Soto, J.A., Takai, H., Mai, S., Elledge, S.J., Motoyama, N., Deng, C.X. EMBO J. (2006) [Pubmed]
  6. Silencing of unsynapsed meiotic chromosomes in the mouse. Turner, J.M., Mahadevaiah, S.K., Fernandez-Capetillo, O., Nussenzweig, A., Xu, X., Deng, C.X., Burgoyne, P.S. Nat. Genet. (2005) [Pubmed]
  7. Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Xu, X., Qiao, W., Linke, S.P., Cao, L., Li, W.M., Furth, P.A., Harris, C.C., Deng, C.X. Nat. Genet. (2001) [Pubmed]
  8. Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Xu, X., Wagner, K.U., Larson, D., Weaver, Z., Li, C., Ried, T., Hennighausen, L., Wynshaw-Boris, A., Deng, C.X. Nat. Genet. (1999) [Pubmed]
  9. Partial rescue of Brca1 (5-6) early embryonic lethality by p53 or p21 null mutation. Hakem, R., de la Pompa, J.L., Elia, A., Potter, J., Mak, T.W. Nat. Genet. (1997) [Pubmed]
  10. Promotion of mammary cancer development by tamoxifen in a mouse model of Brca1-mutation-related breast cancer. Jones, L.P., Li, M., Halama, E.D., Ma, Y., Lubet, R., Grubbs, C.J., Deng, C.X., Rosen, E.M., Furth, P.A. Oncogene (2005) [Pubmed]
  11. Calcitriol derivatives with two different side chains at C-20 III. An epimeric pair of the gemini family with unprecedented antiproliferative effects on tumor cells and renin mRNA expression inhibition. Maehr, H., Uskokovic, M., Adorini, L., Penna, G., Mariani, R., Panina, P., Passini, N., Bono, E., Perego, S., Biffi, M., Holick, M., Spina, C., Suh, N. J. Steroid Biochem. Mol. Biol. (2007) [Pubmed]
  12. Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Hou, D.Y., Muller, A.J., Sharma, M.D., DuHadaway, J., Banerjee, T., Johnson, M., Mellor, A.L., Prendergast, G.C., Munn, D.H. Cancer Res. (2007) [Pubmed]
  13. Inhibition of bone resorption, rather than direct cytotoxicity, mediates the anti-tumour actions of ibandronate and osteoprotegerin in a murine model of breast cancer bone metastasis. Zheng, Y., Zhou, H., Brennan, K., Blair, J.M., Modzelewski, J.R., Seibel, M.J., Dunstan, C.R. Bone (2007) [Pubmed]
  14. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Hakem, R., de la Pompa, J.L., Sirard, C., Mo, R., Woo, M., Hakem, A., Wakeham, A., Potter, J., Reitmair, A., Billia, F., Firpo, E., Hui, C.C., Roberts, J., Rossant, J., Mak, T.W. Cell (1996) [Pubmed]
  15. Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos. Ludwig, T., Chapman, D.L., Papaioannou, V.E., Efstratiadis, A. Genes Dev. (1997) [Pubmed]
  16. Brca2 is required for embryonic cellular proliferation in the mouse. Suzuki, A., de la Pompa, J.L., Hakem, R., Elia, A., Yoshida, R., Mo, R., Nishina, H., Chuang, T., Wakeham, A., Itie, A., Koo, W., Billia, P., Ho, A., Fukumoto, M., Hui, C.C., Mak, T.W. Genes Dev. (1997) [Pubmed]
  17. Brcal required for T cell lineage development but not TCR loci rearrangement. Mak, T.W., Hakem, A., McPherson, J.P., Shehabeldin, A., Zablocki, E., Migon, E., Duncan, G.S., Bouchard, D., Wakeham, A., Cheung, A., Karaskova, J., Sarosi, I., Squire, J., Marth, J., Hakem, R. Nat. Immunol. (2000) [Pubmed]
  18. Impaired meiotic DNA-damage repair and lack of crossing-over during spermatogenesis in BRCA1 full-length isoform deficient mice. Xu, X., Aprelikova, O., Moens, P., Deng, C.X., Furth, P.A. Development (2003) [Pubmed]
  19. Brca1 and Brca2 expression patterns in mitotic and meiotic cells of mice. Blackshear, P.E., Goldsworthy, S.M., Foley, J.F., McAllister, K.A., Bennett, L.M., Collins, N.K., Bunch, D.O., Brown, P., Wiseman, R.W., Davis, B.J. Oncogene (1998) [Pubmed]
  20. Effects of Novel Retinoic Acid Metabolism Blocking Agent (VN/14-1) on Letrozole-Insensitive Breast Cancer Cells. Belosay, A., Brodie, A.M., Njar, V.C. Cancer Res. (2006) [Pubmed]
  21. Environmental carcinogens and p53 tumor-suppressor gene interactions in a transgenic mouse model for mammary carcinogenesis. Medina, D., Ullrich, R., Meyn, R., Wiseman, R., Donehower, L. Environ. Mol. Mutagen. (2002) [Pubmed]
  22. The effect of loss of Brca1 on the sensitivity to anticancer agents in p53-deficient cells. Fedier, A., Steiner, R.A., Schwarz, V.A., Lenherr, L., Haller, U., Fink, D. Int. J. Oncol. (2003) [Pubmed]
  23. Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Poole, A.J., Li, Y., Kim, Y., Lin, S.C., Lee, W.H., Lee, E.Y. Science (2006) [Pubmed]
  24. Mice heterozygous for a Brca1 or Brca2 mutation display distinct mammary gland and ovarian phenotypes in response to diethylstilbestrol. Bennett, L.M., McAllister, K.A., Malphurs, J., Ward, T., Collins, N.K., Seely, J.C., Gowen, L.C., Koller, B.H., Davis, B.J., Wiseman, R.W. Cancer Res. (2000) [Pubmed]
  25. Are Trp53 rescue of Brca1 embryonic lethality and Trp53/Brca1 breast cancer association related? McAllister, K.A., Wiseman, R.W. Breast Cancer Res. (2002) [Pubmed]
  26. BRCA1 facilitates microhomology-mediated end joining of DNA double strand breaks. Zhong, Q., Chen, C.F., Chen, P.L., Lee, W.H. J. Biol. Chem. (2002) [Pubmed]
  27. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. Bhattacharyya, A., Ear, U.S., Koller, B.H., Weichselbaum, R.R., Bishop, D.K. J. Biol. Chem. (2000) [Pubmed]
  28. Stable Knockdown of Estrogen Receptor alpha by Vector-Based RNA Interference Suppresses Proliferation and Enhances Apoptosis in Breast Cancer Cells. Fu, H.J., Jia, L.T., Bao, W., Zhao, J., Meng, Y.L., Wang, C.J., Yao, L.B., Chen, S.Y., Yang, A.G. Cancer Biol. Ther. (2006) [Pubmed]
  29. Snail in the frame of malignant tumor recurrence. De Craene, B., Berx, G. Breast Cancer Res. (2006) [Pubmed]
  30. Laminin-rich extracellular matrix association with mammary epithelial cells suppresses Brca1 expression. O'Connell, F.C., Martin, F. Cell Death Differ. (2000) [Pubmed]
  31. Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability. McCarthy, E.E., Celebi, J.T., Baer, R., Ludwig, T. Mol. Cell. Biol. (2003) [Pubmed]
  32. Steroid Receptor Coactivator-3 and Activator Protein-1 Coordinately Regulate the Transcription of Components of the Insulin-Like Growth Factor/AKT Signaling Pathway. Yan, J., Yu, C.T., Ozen, M., Ittmann, M., Tsai, S.Y., Tsai, M.J. Cancer Res. (2006) [Pubmed]
  33. A targeted mouse Brca1 mutation removing the last BRCT repeat results in apoptosis and embryonic lethality at the headfold stage. Hohenstein, P., Kielman, M.F., Breukel, C., Bennett, L.M., Wiseman, R., Krimpenfort, P., Cornelisse, C., van Ommen, G.J., Devilee, P., Fodde, R. Oncogene (2001) [Pubmed]
  34. Role of the tumor suppressor gene Brca1 in genetic stability and mammary gland tumor formation. Deng, C.X., Scott, F. Oncogene (2000) [Pubmed]
  35. Brca1 and Brca2 protein expression patterns in different tissues of murine origin. Bernard-Gallon, D.J., De Latour, M.P., Sylvain, V., Vissac, C., Aunoble, B., Chassagne, J., Bignon, Y.J. Int. J. Oncol. (2001) [Pubmed]
  36. Mouse Brca1: localization sequence analysis and identification of evolutionarily conserved domains. Abel, K.J., Xu, J., Yin, G.Y., Lyons, R.H., Meisler, M.H., Weber, B.L. Hum. Mol. Genet. (1995) [Pubmed]
  37. Homology-directed dna repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Moynahan, M.E., Cui, T.Y., Jasin, M. Cancer Res. (2001) [Pubmed]
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