Abstract : Germline mutations in the BRCA1 tumor suppressor gene have been implicated in hereditary breast and ovarian cancers. As part of our ultimate goal to characterize novel interactions between BRCA1 and other proteins involved in well-defined pathways, we have pursued an area of research that is just beginning to receive a great deal of attention for BRCA1 function, transcriptional regulation. Since BRCA1-associated cancers typically involve steroid hormone responsive tissues, it is possible that BRCA1 plays a role in steroid receptor signaling. Using transient transfection assays, BRCA1 was found to enhance androgen signaling via activation function-l (AF-1) of the androgen receptor (AR) . Furthermore, coexpression of BRCA1 with p160 nuclear receptor coactivators SRC1a, GRIP1, or AIB1 resulted in synergistic potentiation of androgen receptor and estrogen receptor (ER-a) signaling in both breast and prostate cells. The N-terminal subdomain of BRCA1 physically interacted with both the N-terminal domain of the AR and the C-terminal domain of the p160 nuclear receptor coactivator, GRIP1, by in vitro protein binding and mapping assays. Though further in vivo studies are necessary to determine the physiological significance of these interactions, these results suggest that BRCA1 may play a role in hormone regulation by directly modulating nuclear receptor-p160 coactivator interactions. Therefore, in fulfillment of our ultimate goals, we demonstrate a novel role for BRCA1 in transcriptional regulation which may aid in our understanding of how loss of BRCA1 results in increased neoplastic transformation.