Growth factor signaling pathways modulate BRCA1 repression of estrogen receptor-alpha activity |
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Authors: | Ma Yongxian Hu Changyan Riegel Anna T Fan Saijun Rosen Eliot M |
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Affiliation: | Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C. 20057-1469, USA. |
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Abstract: | 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 underexpression of BRCA1 caused ligand-independent activation of ER-alpha that was mediated through phosphatidylinositol-3 kinase (PI3K)/c-Akt signaling. BRCA1 underexpression 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, an enzyme that dephosphorylates Akt. ERs with point mutations of several growth factor-targeted serine residues (S167A, S118A, and S118/167A) were resistant to repression by BRCA1, although the single point mutant receptors still associated with the BRCA1 protein. The enhanced ER-alpha activity attributable to BRCA1 knockdown was dependent, in part, on 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 on PI3K/Akt signaling and was mimicked by pharmacologic inhibition of protein phosphatase 2A. 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. |
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