The breast cancer susceptibility gene BRCA1 is mutated in about one-half of all hereditary breast cancer cases; and its expression is frequently decreased in sporadic cancers. Previously, we demonstrated a functional interaction between the BRCA1 and estrogen receptor-alpha (ER-alpha) proteins that causes inhibition of ER-alpha signaling. Here, we examined the role of growth factor signaling pathways in modulating this interaction. We found that under-expression of BRCA1 caused ligand-independent activation of ER-alpha that was mediated through phosphatidyl-inositol-3-kinase (PI3K)/c-Akt signaling. BRCA1 under-expression also enhanced estrogen-inducible ER-alpha activity in a PI3K/Akt dependent manner. Exogenous c-Akt conferred estrogen-independent ER-alpha activation and rescued the BRCA1 repression of estrogen-stimulated ER-alpha activity. BRCA1 knockdown stimulated c-Akt activity, in part, by inhibiting the activity of protein phosphatase 2A (PP2A), an enzyme that dephosphorylates Akt. Estrogen receptors with point mutations of several growth factor-targeted serine residues (S167A, S118A, and S118/167A) were resistant to repression by BRCA1, even though the single point mutant receptors still associated with the BRCA1 protein. The enhanced ER-alpha activity due to BRCA1 knockdown was dependent, in part, upon serine residues 167 and 118 of ER-alpha. BRCA1 knockdown caused an increase in ER-alpha phosphorylation on serine-167 [but not serine-118 or serine-104/106)] that was dependent upon PI3K/Akt signaling and was mimicked by pharmacologic inhibition of PP2A. These findings suggest that BRCA1 regulates Akt signaling and the PI3K/Akt pathway modulates the ability of BRCA1 to repress ER-alpha, in part, through serine phosphorylation events in the activation function-1 domain of ER-alpha.