Tyrosine phosphorylation regulates ER? ubiquitination, protein turnover, and inhibition of breast cancer.

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

SUBMITTER: Yuan B 

PROVIDER: S-EPMC5173158 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature