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

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 ER alpha transcriptional program and ER+ breast cancer growth. Mechanistically, the Hippo pathway transcription factor TEAD physically interacts with ER alpha to increase its promoter/enhancer occupancy whereas YAP inhibits ER alpha/TEAD interaction, decreases ER alpha occupancy on its target promoters/enhancers, and promotes ER alpha degradation by the proteasome. Furthermore, YAP inhibits hormone-independent transcription of ER alpha 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 ER alpha mutants, suggesting that targeting the Hippo-YAP-TEAD signaling axis could be a potential therapeutical strategy to overcome endocrine therapy resistance conferred by ER alpha mutants. Recent studies have reported that oncoprotein YAP can function as tumour suppressor in certain contexts. Here the authors show that inhibition of Hippo signalling or YAP activation blocks ER alpha transcriptional program and ER + breast cancer growth and mechanistically this is through YAP interfering with TEAD-ER alpha signalling axis.