Germline alterations in BRCA1, a tumor suppressor gene of unknown function, are associated with an 85-90% lifetime risk of developing female breast cancer. Data from our laboratory and others suggest that BRCA1 is a nuclear phosphoprotein that produces growth inhibition when overexpressed in cultured cell lines. There are additional data that suggest that BRCA1 expression peaks at the G1/S boundary and is barely detectable at other phases of the cell cycle, and that BRCA1 G1/S expression is induced by mitogen exposure. Recent data for our group suggests that BRCA1 activates transcription of the cell growth inhibitor p21, and that p21 is required for the growth inhibitory effects of BRCA1 in a cell culture model. Additionally, they have preliminary evidence that BRCA1 binds to p53, a tumor suppressor known to function as a checkpoint at G1/S. Based on these data, we hypothesize that BRCA1 is a G1/S checkpoint molecule, and at least some of its effects are mediated by p21. The work outlined in this proposal will test this hypothesis by addressing the following specific aims: 1) to define the role of BRCA1 in p21 expression and function in cell cycle regulation, 2) to demonstrate interaction between BRCA1 and p53 and to determine the role of this interaction in p21-dependent and -independent BRCA1 function, and 3) to use the association between BRCA1, p21, and p53 to define the response to DNA damage and regulation of apoptosis. These experiments will define the endpoints of tumor """"""""preventor"""""""" gene that helps maintain genome stability through a p21-dependent pathway. They will extend the observations made in cell culture to a series of 150 archival breast cancers we have collected from BRCA1 mutation carriers to determine the potential clinical relevance of the findings. As an exponentially increasing body of literature suggests that alterations in cell cycle regulation may be a unifying feature of malignant transformation, the studies we propose should provide insight into the role played by BRCA1 in tumor suppression. Identification of the specific lesions in growth regulatory pathways that are altered in BRCA1-associated breast cancer also will define potential preventative and therapeutic targets.
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