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.

Estrogen Receptor Beta (ERβ): A Ligand Activated Tumor Suppressor

“…Phosphorylation of tyrosine 36 is necessary for the tumor suppressor activity of the receptor in U87 glioblastoma cells, MCF7 breast cancer cells, and SKOV3 ovarian cancer cells. Interestingly, phosphorylation of Y36 of ERβ up-regulates its ubiquitination and turnover, suggesting that turnover may be necessary for transcriptional activity (25,26). Similarly, phosphorylation of serine-60 and serine-75 residues increases the degradation of ERβ.…”

Estrogen receptor beta signaling in CD8+ T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch

“…Our published work shows that the ERβ-selective agonist S-equol promotes human ERβ phosphorylation at Y36 in breast cancer cells. 9 S-equol further enhanced TCR-activated ERβ tyrosine phosphorylation in anti-CD3/CD28-stimulated mouse EL4 lymphoma cells ( figure 4A ). In light of in vitro data, we assessed a potential effect of S-equol on boosting antitumor efficacy of αPD-1 in mouse tumor models.…”

A Phosphotyrosine Switch in Estrogen Receptor β Is Required for Mouse Ovarian Function

“…Our previous cancer-related study shows that the ERβ-specific agonist S-equol elevates the same phosphotyrosine switch in cancer cells and antitumor CD8 + T cells and inhibits tumor growth in both xenograft and syngeneic tumor models ( Yuan et al, 2016 , 2021 ). S-equol is a natural compound with proven clinical safety and high tolerance in humans, based on multiple phase I and II clinical trials ( Setchell et al, 2005 ; Jackson et al, 2011 ; Takeda et al, 2018 ).…”

“…So far, several phosphorylation residues, including Y36, S60, S75, S87, and S105, have been identified in human ERβ ( Tremblay et al, 1999 ; Cheng et al, 2000 ; Tremblay and Giguere, 2001 ; St-Laurent et al, 2005 ; Picard et al, 2008 ; Lam et al, 2012 ; Yuan et al, 2014 ). In particular, our published work identified a subtype-specific phosphotyrosine residue in human ERβ Y36 that regulates its tumor-intrinsic ( Yuan et al, 2014 , 2016 ) and -extrinsic ( Yuan et al, 2021 ) antitumor activity, which underscores an ER subtype-specific regulatory mechanism via tyrosine phosphorylation.…”