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A phosphotyrosine switch determines the antitumor activity of ER?.

ABSTRACT: Estrogen receptors ER? and ER? share considerable sequence homology yet exert opposite effects on breast cancer cell proliferation. While the proliferative role of ER? in breast tumors is well characterized, it is not clear whether the antitumor activity of ER? can be mobilized in breast cancer cells. Here, we have shown that phosphorylation of a tyrosine residue (Y36) present in ER?, but not in ER?, dictates ER?-specific activation of transcription and is required for ER?-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 ER? function. A nonphosphorylatable, transcriptionally active ER? mutant retained antitumor activity but circumvented control by upstream regulators. Phosphorylation of Y36 was required for ER?-mediated coactivator recruitment to ER? target promoters. In human breast cancer samples, elevated phosphorylation of Y36 in ER? correlated with high levels of c-ABL but low EYA2 levels. Furthermore, compared with total ER?, the presence of phosphorylated Y36-specific ER? 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 ER?-specific antitumor activity and has potential as both a prognostic tool and a molecular target for cancer therapy.

SUBMITTER: Yuan B

PROVIDER: S-EPMC4109526 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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A phosphotyrosine switch determines the antitumor activity of ERβ.

Yuan Bin B Cheng Long L Chiang Huai-Chin HC Xu Xiaojie X Han Yongjian Y Su Hang H Wang Lingxue L Zhang Bo B Lin Jing J Li Xiaobing X Xie Xiangyang X Wang Tao T Tekmal Rajeshwar R RR Curiel Tyler J TJ Yuan Zhi-Min ZM Elledge Richard R Hu Yanfen Y Ye Qinong Q Li Rong R

The Journal of clinical investigation 20140624 8

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 o ...[more]

PMID: 24960160

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Project description:BackgroundThe non-overlapping functions of the two estrogen receptor subtypes, ERα (Estrogen Receptor α)and ERβ (Estrogen Receptor β), in tumor cells have been studied extensively. However, their counterparts in host cells is vastly underinterrogated. Even less is known about how ERα and ERβ activities are regulated in a subtype-specific manner. We previously identified a phosphotyrosine residue (pY36) of human ERβ that is important for tumor ERβ to inhibit growth of breast cancer cells in vitro and in vivo. A role of this ERβ phosphotyrosine switch in regulating host ERβ remains unclear.Conventional gene editing was used to mutate the corresponding tyrosine residue of endogenous mouse ERβ (Y55F) in mouse embryonic stem cells. The derived homozygous mutant Esr2Y55F/Y55F mouse strain and its wild-type (WT) counterpart were compared in various transplant tumor models for their ability to support tumor growth. In addition, flow cytometry-based immunophenotyping was carried out to assess antitumor immunity of WT and mutant hosts. Adoptive transfer of bone marrow and purified CD8+ T cells were performed to identify the host cell type that harbors ERβ-dependent antitumor function. Furthermore, cell signaling assays were conducted to compare T cell receptor (TCR)-initiated signaling cascade in CD8+ T cells of WT and mutant mice. Lastly, the ERβ-selective agonist S-equol was evaluated for its efficacy to boost immune checkpoint blockade (ICB)-based anticancer immunotherapy.Disabling the ERβ-specific phosphotyrosine switch in tumor-bearing hosts exacerbates tumor growth. Further, a cell-autonomous ERβ function was defined in CD8+ effector T cells. Mechanistically, TCR activation triggers ERβ phosphorylation, which in turn augments the downstream TCR signaling cascade via a non-genomic action of ERβ. S-equol facilitates TCR activation that stimulates the ERβ phosphotyrosine switch and boosts anti-PD-1 (Programmed cell death protein 1) ICB immunotherapy.Our mouse genetic study clearly demonstrates a role of the ERβ phosphotyrosine switch in regulating ERβ-dependent antitumor immunity in CD8+ T cells. Our findings support the development of ERβ agonists including S-equol in combination with ICB immunotherapy for cancer treatment.

Dataset Information

A phosphotyrosine switch determines the antitumor activity of ER?.

Publications

A phosphotyrosine switch determines the antitumor activity of ERβ.

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