The long-term objective of this proposal is to determine the tumor suppressor functions of the hereditary breast/ovarian cancer susceptibility gene, BRCA1. A breast cancer cell line lacking wild-type BRCA1, HCC1937, shows a defect in double strand break repair (DSBR). Wild-type but not cancer-predisposing alleles of BRCA1, stably expressed in HCC1937 cells, correct this defect. This suggests that the DSBR functions of BRCA1 are tumor suppressor functions. Work proposed here will elucidate the function of BRCA1 in DSBR, by use of specific quantitative assays of recombination in HCC1937 cells (Aim 1). To this end, this laboratory has developed a novel recombinational reporter that can positively select for recombination events arising between sister chromatids. The goal is to determine which recombination functions in HCC1937 cells are BRCA1-- dependent (Aim 1) and to perform a genetic analysis of these BRCA1- dependent recombination functions (Aim 2). Defects in recombination frequently cause increased mutation rates in other genes. The mutagenic consequences of BRCA1 dysfunction will be assessed in several parallel systems (Aim 3). This work will therefore significantly advance our understanding of how BRCA1 acts as a tumor suppressor gene.
The specific aims are: 1. To determine the recombinational mechanisms by which wtBRCA1 restores DSBR to HCC1937 cells. 2. To define domains of BRCA1 that are important for recombination. 3. To determine the effect of BRCA1 germline mutation upon the rate and pattern of mutation in other genes.
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