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

Abstract	Unlike estrogen receptor α (ERα) that predominantly promotes hormone-dependent breast tumor growth, ERβ exhibits antitumor effects in a variety of cancer types. We recently identified a phosphotyrosine residue in ERβ, but not ERα, that dictates ERβ transcriptional activity and antitumor function. We show here that this ER isotype-specific phosphotyrosine switch is important for regulating ERβ activity in cell proliferation, migration, and invasion. At the mechanistic level, phosphorylated ERβ, which recruits transcriptional coactivator p300, is in turn targeted by p300 for ubiquitination and proteasome-dependent protein turnover. Furthermore, ERβ-specific agonists such as S-equol enhance ERβ phosphorylation, suggesting a crosstalk between ligand- and posttranslational modification-dependent ERβ activation. Inhibition of xenograft tumor growth by S-equol is associated with reduced tumor Ki-67 expression and elevated ERβ tyrosine phosphorylation. Taken together, our data support the notion that phosphotyrosine-dependent ERβ signaling is an attractive target for anticancer treatment.
Authors	Bin Yuan, Long Cheng, Kshama Gupta, Huai-Chin Chiang, Harshita B Gupta, Gangadhara R Sareddy, Degeng Wang, Kate Lathrop, Richard Elledge, Pei Wang, Stanton McHardy, Ratna Vadlamudi, Tyler J Curiel, Yanfen Hu, Qinong Ye, Rong Li
Journal	Oncotarget (Oncotarget) Vol. 7 Issue 27 Pg. 42585-42597 (Jul 05 2016) ISSN: 1949-2553 [Electronic] United States
PMID	27323858 (Publication Type: Journal Article)
Chemical References	Antineoplastic Agents ESR2 protein, human Estrogen Receptor beta Ki-67 Antigen Ligands Phosphotyrosine Tyrosine p300-CBP Transcription Factors Proteasome Endopeptidase Complex
Topics	Animals Antineoplastic Agents (therapeutic use) Breast Neoplasms (drug therapy, metabolism, pathology) Cell Proliferation Cell Survival Estrogen Receptor beta (metabolism) Female HEK293 Cells Humans Ki-67 Antigen (metabolism) Ligands MCF-7 Cells Mice Mice, Nude Neoplasm Transplantation Phosphorylation Phosphotyrosine (chemistry) Proteasome Endopeptidase Complex (metabolism) Tyrosine (chemistry) Ubiquitination p300-CBP Transcription Factors (metabolism)

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