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YAP inhibits ERα and ER+ breast cancer growth by disrupting a TEAD-ERα signaling axis

Author

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  • Xu Li

    (University of Texas Southwestern Medical Center)

  • Shu Zhuo

    (University of Texas Southwestern Medical Center
    Harvard School of Dental Medicine
    Signet Therapeutics Inc., Research Institute of Tsinghua University In Shenzhen, Shenzhen)

  • Ting Zhuang

    (Xinxiang Medical University)

  • Yong Suk Cho

    (University of Texas Southwestern Medical Center)

  • Guojin Wu

    (University of Texas Southwestern Medical Center)

  • Yuchen Liu

    (Harvard School of Dental Medicine
    Harvard Stem Cell Institute
    Dana-Farber/Harvard Cancer Center)

  • Kun Mu

    (Qilu Hospital, Cheeloo College of Medicine, Shandong University
    School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University)

  • Kai Zhang

    (Qilu Hospital, Cheeloo College of Medicine, Shandong University)

  • Peng Su

    (Qilu Hospital, Cheeloo College of Medicine, Shandong University)

  • Yingzi Yang

    (Harvard School of Dental Medicine
    Harvard Stem Cell Institute
    Dana-Farber/Harvard Cancer Center)

  • Cheng Cheng Zhang

    (University of Texas Southwestern Medical Center)

  • Jian Zhu

    (University of Texas Southwestern Medical Center
    Xinxiang Medical University
    Cheeloo College of Medicine, Shandong University)

  • Jin Jiang

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

Abstract

Hippo signaling restricts tissue growth by inhibiting the transcriptional effector YAP. Here we uncover a role of Hippo signaling and a tumor suppressor function of YAP in estrogen receptor positive (ER+) breast cancer. We find that inhibition of Hippo/MST1/2 or activation of YAP blocks the ERα transcriptional program and ER+ breast cancer growth. Mechanistically, the Hippo pathway transcription factor TEAD physically interacts with ERα to increase its promoter/enhancer occupancy whereas YAP inhibits ERα/TEAD interaction, decreases ERα occupancy on its target promoters/enhancers, and promotes ERα degradation by the proteasome. Furthermore, YAP inhibits hormone-independent transcription of ERα gene (ESR1). Consistently, high levels of YAP correlate with good prognosis of ER+ breast cancer patients. Finally, we find that pharmacological inhibition of Hippo/MST1/2 impeded tumor growth driven by hormone therapy resistant ERα mutants, suggesting that targeting the Hippo-YAP-TEAD signaling axis could be a potential therapeutical strategy to overcome endocrine therapy resistance conferred by ERα mutants.

Suggested Citation

  • Xu Li & Shu Zhuo & Ting Zhuang & Yong Suk Cho & Guojin Wu & Yuchen Liu & Kun Mu & Kai Zhang & Peng Su & Yingzi Yang & Cheng Cheng Zhang & Jian Zhu & Jin Jiang, 2022. "YAP inhibits ERα and ER+ breast cancer growth by disrupting a TEAD-ERα signaling axis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30831-5
    DOI: 10.1038/s41467-022-30831-5
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    References listed on IDEAS

    as
    1. Yong suk Cho & Jian Zhu & Shuangxi Li & Bing Wang & Yuhong Han & Jin Jiang, 2018. "Regulation of Yki/Yap subcellular localization and Hpo signaling by a nuclear kinase PRP4K," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    2. Shenghong Ma & Zhengming Wu & Feng Yang & Jianmin Zhang & Randy L. Johnson & Michael G. Rosenfeld & Kun-Liang Guan, 2021. "Hippo signalling maintains ER expression and ER+ breast cancer growth," Nature, Nature, vol. 591(7848), pages 1-10, March.
    3. Dana Elster & Marie Tollot & Karin Schlegelmilch & Alessandro Ori & Andreas Rosenwald & Erik Sahai & Björn von Eyss, 2018. "TRPS1 shapes YAP/TEAD-dependent transcription in breast cancer cells," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
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