Epigenetic and Transcriptional Response to HDAC Inhibition in Triple Negative Breast Cancer Cells
Walheim, Danielle Marie
Evidence suggests that chromatin-modifying complexes contribute to the uncontrolled cell proliferation of cancer cells through dysregulation of the epigenome. Histone deacetylases (HDACs) are a type of chromatin modifying complex that are responsible for removing acetyl groups from modified histone tails. Their dysregulation is known to play a role in oncogenesis of many cancer types by contributing to an aberrant epigenome and transcription program. Recent clinical trials have begun to test the efficacy of using HDACi’s to treat certain breast cancer, but their application to an aggressive type of breast cancer (Triple Negative Breast Cancer, TNBC) has largely been overlooked. My thesis project aims to test the hypothesis that increased chromatin acetylation associated with Panobinostat treatment leads to increased TSG expression and growth inhibition. Here I analyze the phenotypic effect of Panobinostat (an HDACi) in TNBC preclinical models, and found that Panobinostat is a potent anti-cancer agent for a broad panel of TNBC subtypes. I also observed histone acetylation increases in TNBC cells in a dose-dependent manner in response to Panobinostat. After examining bulk histone acetylation levels from nuclear extracts, I examined genome-wide Panobinostat-dependent H3K27Ac changes to identify differentially affected enhancers and promoters. Expression profiling corroborated the observed Pan-dependent epigenetic changes and gene-ontology analysis revealed deregulated tumor suppressor genes and perturbed signaling pathways. In summary, my thesis provides new insights in how Panobinostat leads to impaired TNBC cell growth, presents evidence for H3K27ac associated activity, and provides a rationale for the design of combinatorial drug therapies for TNBC.