A phosphotyrosine switch determines the antitumor activity of ERβ.

Estrogen receptors ER alpha and ER beta-share considerable sequence homology yet exert opposite effects on breast cancer cell proliferation. While the proliferative role of ER alpha in breast tumors is well characterized, it is not clear whether the antitumor activity of ER beta can be mobilized in breast cancer cells. Here, we have shown that phosphorylation of a tyrosine residue (Y36) present in ER beta, but not in ER alpha, dictates ER beta-specific activation of transcription and is required for ER beta-dependent inhibition of cancer cell growth in culture and in murine xenografts. Additionally, the c-ABL tyrosine kinase and EYA2 phosphatase directly and diametrically controlled the phosphorylation status of Y36 and subsequent ER beta function. A nonphosphorylatable, transcriptionally active ER beta mutant retained antitumor activity but circumvented control by upstream regulators. Phosphorylation of Y36 was required for ER beta-mediated coactivator recruitment to ER beta target promoters. In human breast cancer samples, elevated phosphorylation of Y36 in ER beta correlated with high levels of c-ABL but low EYA2 levels. Furthermore, compared with total ER beta, the presence of phosphorylated Y36-specific ER beta was strongly associated with both disease-free and overall survival in patients with stage II and III disease. Together, these data identify a signaling circuitry that regulates ER beta-specific antitumor activity and has potential as both a prognostic tool and a molecular target for cancer therapy.