The Role of BRCA1 in Normal Mammary Epithelial Development and Tumorigenesis.
Annual rept. 1 Jun 98-31 May 99
NORTH CAROLINA UNIV AT CHAPEL HILL
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Breast cancer is the most common serious malignancy affecting women, afflicting an estimated one in eight women by the age of 95. Women with a germline mutation in BRCA1 have an estimated 80-90 overall lifetime risk for developing breast cancer. Despite extensive study since 1994, the function of BRCA1 has not yet been established. Numerous studies have suggested an interaction between BRCA1 and p53. To determine if mutations in p53 enhance tumorigenesis in BRCA1-deficient mice, I have generated mice with germline mutations in both Brca1 and p53. We and other groups have shown that homozygosity for a Brca1 mutation results in embryonic lethality regardless of the p53 status. However, following extensive breeding, three Brca1--p53--mice have survived to adulthood in our colony. The survival of these mice has allowed us to address specific questions regarding the function of BRCA1. The first is to determine the mechanism by which loss of BRCA1 alters the growth of normal cells. The second is to determine how this normal function of BRCA1 is related to its role in tumorigenesis, a role supported by the loss of homozygosity seen in most tumors of patients with inherited BRCA1 mutations.
- Anatomy and Physiology
- Medicine and Medical Research