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 (HDACi) have shown clinical benefit in HR ( +) breast cancer patients. The Hippo pathway is an important cellular pathway involving proliferation, cell contact, and cancer. 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. Few studies have investigated the link between HDACi and the Hippo pathway. In our study, we demonstrate that HDACi induces transcriptional downregulation of YAP expression, while conversely activating a TEAD-mediated transcriptional program with upregulation of canonical Hippo pathway genes. We subsequently identified four Hippo canonical genes (CCDC80, GADD45A, F3, and TGFB2) that were upregulated by HDACi and associated with significantly improved survival in a HR ( +) breast cancer cohort. We further validated experimentally that HR ( +) breast cancer cells treated with HDACi resulted in upregulation of CCDC80 and GADD45A. A pan-cancer analysis of TCGA database demonstrated lower CCDC80 and GADD45A expression in tumor tissue compared to non-tumor samples in BRCA (breast cancer), LAML (acute myeloid leukemia), and UCS (uterine carcinosarcoma). Further analysis of HR ( +) breast cancer patients in the METABRIC dataset revealed high CCDC80 and/or GADD45A expression associated with significantly better survival outcomes compared to patients with low expression. Our study provides evidence for a novel mechanism of HDACi clinical activity, as well as a potential role for CCDC80 and GADD45A in HR ( +) breast cancer.