HDAC inhibitors modulate Hippo pathway signaling in hormone positive breast cancer

Breast cancer has constantly been the leading causes of death in women, and hormone receptor (HR) positive, HER2 negative is the majority subtype. Histone deacetylase (HDAC) inhibitors have shown clinical benefit in HR (+) breast cancer patients. The hippo pathway proteins YAP/TAZ are often viewed as pro-tumorigenic, however, recent studies support a role of YAP as a tumor suppressor in HR (+) breast cancer downregulation of estrogen receptor (ER) expression. Few studies have investigated the link between HDACi and the Hippo pathway. In our study, we demonstrate that HDAC inhibitors induce transcriptional down-regulation of YAP expression, while conversely activating a TEAD mediated transcriptional program with upregulation of canonical Hippo pathway genes. We further identified 4 Hippo canonical genes (CCDC80, GADD45A, F3, TGFB2) that were upregulated by HDAC inhibitors and associated with significantly improved survival in a HR (+) breast cancer cohort. Patients with high CCDC80 or GADD45A expression had significantly better survival outcomes compared to patients with low expression. Our study provides a novel mechanism of action for the clinical benefit of HDAC inhibitors, while providing further experimental support that Hippo-TEAD transcriptional activation is associated with better outcomes in HR (+) breast cancer.