A phosphotyrosine switch determines the antitumor activity of ERβ
Bin Yuan, … , Qinong Ye, Rong Li
Bin Yuan, … , Qinong Ye, Rong Li
Published June 24, 2014
Citation Information: J Clin Invest. 2014;124(8):3378-3390. https://doi.org/10.1172/JCI74085.
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Research Article Oncology

A phosphotyrosine switch determines the antitumor activity of ERβ

Abstract

Estrogen receptors ERα and ERβ share considerable sequence homology yet exert opposite effects on breast cancer cell proliferation. While the proliferative role of ERα in breast tumors is well characterized, it is not clear whether the antitumor activity of ERβ can be mobilized in breast cancer cells. Here, we have shown that phosphorylation of a tyrosine residue (Y36) present in ERβ, but not in ERα, dictates ERβ-specific activation of transcription and is required for ERβ-dependent inhibition of cancer cell growth in culture and in murine xenografts. Additionally, the c-ABL tyrosine kinase and EYA2 phosphatase directly and diametrically controlled the phosphorylation status of Y36 and subsequent ERβ function. A nonphosphorylatable, transcriptionally active ERβ mutant retained antitumor activity but circumvented control by upstream regulators. Phosphorylation of Y36 was required for ERβ-mediated coactivator recruitment to ERβ target promoters. In human breast cancer samples, elevated phosphorylation of Y36 in ERβ correlated with high levels of c-ABL but low EYA2 levels. Furthermore, compared with total ERβ, the presence of phosphorylated Y36–specific ERβ was strongly associated with both disease-free and overall survival in patients with stage II and III disease. Together, these data identify a signaling circuitry that regulates ERβ-specific antitumor activity and has potential as both a prognostic tool and a molecular target for cancer therapy.

Authors

Bin Yuan, Long Cheng, Huai-Chin Chiang, Xiaojie Xu, Yongjian Han, Hang Su, Lingxue Wang, Bo Zhang, Jing Lin, Xiaobing Li, Xiangyang Xie, Tao Wang, Rajeshwar R. Tekmal, Tyler J. Curiel, Zhi-Min Yuan, Richard Elledge, Yanfen Hu, Qinong Ye, Rong Li

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Figure 1

EYA2 modulates the transcriptional activity of ERβ but not ERα.

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EYA2 modulates the transcriptional activity of ERβ but not ERα. (A) Co-I...
(A) Co-IP of endogenous EYA2 and ERβ in a substrain of an MCF7 breast cancer cell line that expresses both ER proteins. E2 (10 nM) was used. (B) GST-EYA2 pulldown with in vitro–translated ERβ in the presence of vehicle or various ligands. Five percent input protein was loaded. An ERα-specific agonist, PPT (1 nM), or an ERβ-specific agonist, DPN (10 nM), was used. (C) Real-time RT-PCR assessed the effect of EYA2 overexpression on ERβ-mediated transcription of its target genes MDA7 and pS2 in MCF7 cells. The value for column 1 was set at 1. (D) Effects of EYA2 knockdown on ERβ-mediated transcription of MDA7 and pS2 in MCF7 cells. *P < 0.05; **P < 0.01. Gel images in this and the following figures are representatives of at least 3 independent experiments. Graphs throughout the figures represent the average of at least 3 experiments. Error bars represent SEM.