ERβ-Specific Function Is Controlled by a Phosphotyrosine Switch

In contrast to estrogen receptor (ER) α, ERβ inhibits proliferation during mammary gland development and suppresses breast cancer cell growth. However, the mechanisms underlying the differential regulation of ERα- and ERβ-specific function remain unclear. Yuan, Cheng, and colleagues found that the tyrosine phosphatase eyes absent homolog 2 (EYA2) specifically interacted with and repressed the transcriptional activity of ERβ but not ERα. This negative regulation of ERβ was dependent on EYA2-mediated dephosphorylation of ERβ at Tyr36, a residue not present in ERα, and was opposed by the kinase activity of c-ABL, which was required for phosphorylation of ERβ Tyr36 and stimulation of ligand-induced transcription of ERβ target genes. Phosphorylation of Tyr36 enhanced the transcriptional activity of ERβ by promoting its interaction with the coactivator p300 and increasing recruitment of p300 to the promoters of ERβ-regulated target genes. In addition, Tyr36 phosphorylation was required for the inhibition of breast cancer cell growth by ERβ. Inhibition of this modification via mutation of Tyr36 to phenylalanine abolished both the transcriptional and antitumor functions of ERβ, whereas a nonphosphorylatable, transcriptionally active ERβ mutant, in which Tyr36 was substituted by glutamate, was insensitive to regulation by EYA2 and c-ABL and maintained the ability to inhibit the growth of breast cancer cell lines and xenograft tumors. Moreover, phosphorylation of ERβ at Tyr36 was inversely associated with tumor size and increased tumor grade and was more strongly correlated with prolonged disease-free and overall survival compared with total ERβ levels in patients with stage II or III breast cancer, suggesting that this modification may be clinically useful as a prognostic marker. These findings identify a phosphotyrosine switch as a critical regulator of ERβ function and suggest that stimulation of the antitumor activity of ERβ may represent a beneficial therapeutic approach in breast cancer.

Yuan B, Cheng L, Chiang HC, Xu X, Han Y, Su H, et al. A phosphotyrosine switch determines the antitumor activity of ERβ. J Clin Invest 2014;124:3378–90.

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