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

  • Nat Commun. 2022 Jun 2;13(1):3075. doi: 10.1038/s41467-022-30831-5.
Xu Li   #  1 ,  Shu Zhuo   #  1  2  3 ,  Ting Zhuang   #  4 ,  Yong Suk Cho  1 ,  Guojin Wu  5 ,  Yuchen Liu  2  6  7 ,  Kun Mu  8  9 ,  Kai Zhang  10 ,  Peng Su  8 ,  Yingzi Yang  2  6  7 ,  Cheng Cheng Zhang  5 ,  Jian Zhu   #  11  12  13 ,  Jin Jiang  14  15
Affiliations
  • 1. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 2. Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Ave, Boston, MA, 02215, USA.
  • 3. Signet Therapeutics Inc., Research Institute of Tsinghua University In Shenzhen, Shenzhen, Guangdong, 518057, PR China.
  • 4. Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453000, PR China.
  • 5. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 6. Harvard Stem Cell Institute, 188 Longwood Ave, Boston, MA, 02215, USA.
  • 7. Dana-Farber/Harvard Cancer Center, 188 Longwood Ave, Boston, MA, 02215, USA.
  • 8. Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China.
  • 9. Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China.
  • 10. Department of Breast Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China.
  • 11. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
  • 12. Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453000, PR China. [email protected].
  • 13. Department of General Surgery, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China. [email protected].
  • 14. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
  • 15. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
  • # Contributed equally.
PMID: 35654829 DOI: 10.1038/s41467-022-30831-5
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.

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