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.
Highlights
The diverse physiological and pathological effects of estrogens are mediated by two estrogen receptors, ERα and ERβ, which are encoded by different genes (ESR1 and ESR2) [1]
In addition to common target genes shared by these two ER isotypes, ERβ binds to its own transcriptional target genes through either estrogen response elements (ERE) or by tethering to other DNA-binding transcription factors [8,9,10,11,12,13,14,15,16,17,18,19]
We found that ERβ-mediated inhibition of both tumor cell migration and invasion were significantly compromised by the Y36F mutation in MCF7 cells (Figure 1C–1D), implicating a role of the phosphotyrosine switch in multiple aspects of ERβmediated antitumor function
Summary
The diverse physiological and pathological effects of estrogens are mediated by two estrogen receptors, ERα and ERβ, which are encoded by different genes (ESR1 and ESR2) [1]. These two ER isotypes share homologous protein sequence and similar transcriptional activity, they exhibit quite distinct biological functions in cancer development and progression. In ERα-positive cancer cells, ERβ is capable of interfering with ERα activity through hetero-dimerization and/or competition for common binding sites [6, 14, 15, 20,21,22,23,24,25,26,27,28,29,30], making ERβ a partial dominant negative receptor for ERα [23, 24, 31]. ERβ functions in transcription and cancer are different from those of ERα
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