Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Ave, Boston, MA, 02215, USA.
Nat Commun. 2022 Jun 2;13(1):3075. doi: 10.1038/s41467-022-30831-5.
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.
Hippo 信号通路通过抑制转录效应因子 YAP 来限制组织生长。在这里，我们揭示了 Hippo 信号通路和 YAP 的肿瘤抑制功能在雌激素受体阳性（ER）乳腺癌中的作用。我们发现，抑制 Hippo/MST1/2 或激活 YAP 可以阻断 ERα 转录程序和 ER 乳腺癌的生长。在机制上，Hippo 通路转录因子 TEAD 与 ERα 物理相互作用，增加其启动子/增强子占有率，而 YAP 抑制 ERα/TEAD 相互作用，降低 ERα 在其靶启动子/增强子上的占有率，并通过蛋白酶体促进 ERα 的降解。此外，YAP 抑制 ERα 基因（ESR1）的激素非依赖性转录。一致地，YAP 的高表达水平与 ER 乳腺癌患者的良好预后相关。最后，我们发现 Hippo/MST1/2 的药理学抑制作用阻碍了激素治疗耐药性 ERα 突变体驱动的肿瘤生长，这表明靶向 Hippo-YAP-TEAD 信号轴可能是克服 ERα 突变体赋予的内分泌治疗耐药性的潜在治疗策略。
