Tyrosine phosphorylation regulates ERβ ubiquitination, protein turnover, and inhibition of breast cancer

Unlike estrogen receptor beta (ER beta) that predominantly promotes hormone-dependent breast tumor growth, ER beta exhibits antitumor effects in a variety of cancer types. We recently identified a phosphotyrosine residue in ER beta, but not ER alpha, that dictates ER beta transcriptional activity and antitumor function. We show here that this ER isotype-specific phosphotyrosine switch is important for regulating ER beta activity in cell proliferation, migration, and invasion. At the mechanistic level, phosphorylated ER beta, which recruits transcriptional coactivator p300, is in turn targeted by p300 for ubiquitination and proteasome-dependent protein turnover. Furthermore, ER beta-specific agonists such as S-equol enhance ER beta phosphorylation, suggesting a crosstalk between ligand- and posttranslational modification-dependent ER beta activation. Inhibition of xenograft tumor growth by S-equol is associated with reduced tumor Ki-67 expression and elevated ER beta tyrosine phosphorylation. Taken together, our data support the notion that phosphotyrosine-dependent ER beta signaling is an attractive target for anticancer treatment.