Phosphorylation by p38 Mitogen-Activated Protein Kinase Promotes Estrogen Receptor α Turnover and Functional Activity via the SCFSkp2 Proteasomal Complex

The nuclear hormone receptor estrogen receptor alpha (ER alpha) mediates the actions of estrogens in target cells and is a master regulator of the gene expression and proliferative programs of breast cancer cells. The presence of ER alpha in breast cancer cells is crucial for the effectiveness of endocrine therapies, and its loss is a hallmark of endocrine-insensitive breast tumors. However, the molecular mechanisms underlying the regulation of the cellular levels of ER alpha are not fully understood. Our findings reveal a unique cellular pathway involving the p38 mitogen-activated protein kinase (p38MAPK) -mediated phosphorylation of ER alpha at Ser-294 that specifies its turnover by the SCFSkp2 proteasome complex. Consistently, we observed an inverse relationship between ER alpha and Skp2 or active p38MAPK in breast cancer cell lines and human tumors. ER alpha regulation by Skp2 was cell cycle stage dependent and critical for promoting the mitogenic effects of estradiol via ER alpha. Interestingly, by the knockdown of Skp2 or the inhibition of p38MAPK, we restored functional ER alpha protein levels and the control of gene expression and proliferation by estrogen and antiestrogen in ER alpha-negative breast cancer cells. Our findings highlight a novel pathway with therapeutic potential for restoring ER alpha and the responsiveness to endocrine therapy in some endocrine-insensitive ER alpha-negative breast cancers.