The role of the BRCA1 and BRCA2 genes in the pathogenesis of breast cancer

Brody, Lawrence

Abstract

Research in the Molecular Pathogenesis is focused on defining changes in the genes that underlie inherited susceptibilities to common diseases such as cancer, heart disease and birth defects. Currently under investigation are genes involved in inherited breast and ovarian cancer. Studies are designed to better understand the function and genetics of the BRCA1 and BRCA2 genes. Patients with familial breast and ovarian cancer are being screened for mutations in these genes. The biological function of the BRCA1 protein is currently unknown. This question is being addressed at the whole animal and biochemical level. A line of mice with a deletion in BRCA1 have been created. The mice are being bred with other tumor susceptible mice. Tumors from these mice will be tested for somatic mutations using comparative genome hybridization and spectral karyotyping. We have purified a portion of this protein used it to screen for other proteins that specifically interact with the BRCA1 protein. We have demonstrated that BRCA1 interacts with other proteins involved in chromatin remodeling and DNA repair including histone deactylase. An increased understanding of these genes will lead to improved diagnostic procedures and possible preventative therapies.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Human Genome Research Institute (NHGRI)
• Type: Intramural Research (Z01)
• Project #: 1Z01HG000120-02
• Application #: 6109046
• Study Section: Special Emphasis Panel (GMBB)
• Support Year: 2
• Fiscal Year: 1998

Institution

• Name: National Human Genome Research Institute
• Country: United States

Publications

Cotton, Richard G H; 2006 Human Variome Project; Appelbe, William et al. (2007) Recommendations of the 2006 Human Variome Project meeting. Nat Genet 39:433-6

Alter, Blanche P; Rosenberg, Philip S; Brody, Lawrence C (2007) Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet 44:1-9

Brody, Lawrence C (2005) Treating cancer by targeting a weakness. N Engl J Med 353:949-50

Coyne, Robert S; McDonald, Heather B; Edgemon, Keith et al. (2004) Functional characterization of BRCA1 sequence variants using a yeast small colony phenotype assay. Cancer Biol Ther 3:453-7

Kanaan, Yasmine; Kpenu, Elikem; Utley, Kim et al. (2003) Inherited BRCA2 mutations in African Americans with breast and/or ovarian cancer: a study of familial and early onset cases. Hum Genet 113:452-60

Szabo, C; Masiello, A; Ryan, J F et al. (2000) The breast cancer information core: database design, structure, and scope. Hum Mutat 16:123-31

Tian, H; Brody, L C; Mao, D et al. (2000) Effective capillary electrophoresis-based heteroduplex analysis through optimization of surface coating and polymer networks. Anal Chem 72:5483-92

Tian, H; Brody, L C; Landers, J P (2000) Rapid detection of deletion, insertion, and substitution mutations via heteroduplex analysis using capillary- and microchip-based electrophoresis. Genome Res 10:1403-13

Tian, H; Jaquins-Gerstl, A; Munro, N et al. (2000) Single-strand conformation polymorphism analysis by capillary and microchip electrophoresis: a fast, simple method for detection of common mutations in BRCA1 and BRCA2. Genomics 63:25-34

Maor, S B; Abramovitch, S; Erdos, M R et al. (2000) BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: potential interaction between BRCA1 and Sp1. Mol Genet Metab 69:130-6