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

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 () and Jin Jiang ()
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Xu Li: University of Texas Southwestern Medical Center
Shu Zhuo: University of Texas Southwestern Medical Center
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
Kun Mu: Qilu Hospital, 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
Cheng Cheng Zhang: University of Texas Southwestern Medical Center
Jian Zhu: University of Texas Southwestern Medical Center
Jin Jiang: University of Texas Southwestern Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30831-5

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