Inducible Transgenic Models of BRCA1 Function
Abstract
Genetic analysis of families in which multiple individuals have developed breast cancer suggests that 5-10% of breast cancer cases result from the inheritance of germline mutations in autosomal dominant susceptibility genes. Germline mutations in one of these breast cancer susceptibility genes, BRCAl, appear to account for most families with inherited breast and ovarian cancer, and somewhat less than half of families displaying inherited breast cancer alone. The BRCAl gene encodes a 220 kDa phosphoprotein that contains a RING finger motif, a transcriptional activation domain, and a BRCT domain typically found in proteins involved in cell cycle regulation and DNA damage response. Tumors arising in patients with germline BRCA1 mutations almost invariably display loss of the wild-type BRCAl allele, suggesting that BRCA1 is a tumor suppressor gene.. Taken together with findings that reduction in BRCAl expression in vitro results in accelerated growth of breast and ovarian cancer cell lines, and that overexpression of BRCAl results in inhibited growth of such cell lines, these observations are consistent with a model in which BRCAl negatively regulates proliferation in adult tissues. Interestingly, however, we have found that the murine homologue of BRCAl is expressed at highest levels in the mouse in cellular compartments containing rapidly proliferating cells undergoing differentiation, such as are found in the breast during puberty and pregnancy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 1998
- Accession Number
- ADB243024
Entities
People
- Lewis A Chodosh
Organizations
- University of Pennsylvania