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 HDACiâs 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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03042016-133830 |
| Date | 11 March 2016 |
| Creators | Walheim, Danielle Marie |
| Contributors | P. Anthony Weil, Gregor Neuert |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03042016-133830/ |
| Rights | restrictone, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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