Author ORCID Identifier


Defense Date


Document Type


Degree Name

Doctor of Philosophy


Microbiology & Immunology

First Advisor

David A. Gewirtz


Anti-estrogens or aromatase inhibitors in combination with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are the current standard of care for estrogen receptor-positive (ER+) Her-2 negative metastatic breast cancer. In triple negative breast cancer, cytotoxic drugs and ionizing radiation are often used as standard of care. Although these therapies prolong progression-free survival, the growth-arrested state of residual tumor cells is clearly transient. Tumor cells that escape what might be considered a dormant state and regain proliferative capacity often acquire resistance to further therapies. Epigenetic regulation can modulate the effects of cancer therapeutics. Our studies are based upon the observation that breast tumor cells arrested by Fulvestrant + Palbociclib enter into states of both autophagy and senescence from which a subpopulation ultimately escapes, potentially contributing to recurrent disease. Autophagy inhibition utilizing pharmacologic or genetic approaches only moderately enhanced the response to Fulvestrant + Palbociclib in ER+ MCF-7 breast tumor cells, slightly delaying proliferative recovery. In contrast, the epigenetic regulator and BET inhibitor/degrader, ARV-825, prolonged the growth-arrested state in both p53 wild-type MCF-7 cells and p53 mutant T-47 D cells and significantly delayed proliferative recovery. In addition, ARV-825 added after the Fulvestrant + Palbociclib combination promoted apoptosis. We further studied another epigenetic regulator, a bromodomain PHD finger transcription factor subunit (BPTF) of the nucleosome remodeling factor (NURF), which promotes resistance to chemotherapies in triple negative breast cancer. We observed sensitization topoisomerase II (TOP2) inhibitors doxorubicin, etoposide, as well as microtubule poisons paclitaxel, vinorelbine, and vinblastine. The observed sensitization appeared to be specific to these mechanisms of action and indicates a potential role of autophagy in these treatments. These studies indicate that the administration of epigenetic regulators, such as BET and NURF inhibition, may potentially improve the standard of care therapy in metastatic ER+ breast cancer and triple negative breast cancer patients and may further prolong progression-free survival.


© Ryan M Finnegan

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