Mechanism of Estrogen Receptor α Regulation

Estrogen operates through estrogen receptors (ER) α and β, which belong to the superfamily of steroid nuclear receptor transcription factors and operate by recruiting cofactors, which form complexes that bind to target genes. Post translational modifications play a role in directing ER activation. We demonstrate that a phospho-mimetic S305E induces ERα activity in the absence of ligand, and enhances activity with estradiol above wild-type. This activation also results cofactor binding and an increase in cell proliferation. We identified a novel protein interaction between ERα and the focal adhesion associated protein zyxin. Zyxin acts as a coactivator by increasing ERá activation. We also demonstrate that mutating the acetylation site of ERα K303 results in downregulation of phosphorylated p38, suggesting a link ERα between and p38 MAPK pathway. Together these data suggest that regulation of the receptor is linked to several kinase mediated signaling pathways and has role in breast cancer progression.