The breast cancer susceptibility genes BRCA1 and BRCA2 account for the majority of familial breast cancers.  The recent isolation of these genes by positional cloning has made it possible to investigate their functions as tumor suppressors and their impact on prognosis and treatment of breast cancer.  We have generated evidence that both BRCA1 and 2 activate transcription of a specific subset of genes and have produced immunological reagents for the detection of the BRCA2 product.  One major aim of this proposal is to elucidate mechanisms by which BRCA1 and 2 alter gene expression, including their interactions with other proteins.  Studies in tissue culture will determine the subcellular localization of BRCA2 as well as the effects of increased or decreased expression of BRCA1 and 2 on biological responses to stress, radiation, therapeutic agents, and hormonal stimuli.  Effort will also be made to establish cell lines from patients with familial breast cancer in order to characterize the effects of wild type gene expression in tumors in which BRCA1 or 2 functions have been inactivated.  The knowledge gained should be useful in developing detection and treatment strategies specifically targeted to heritable breast cancers.