All ETDs from UAB

Advisory Committee Chair

Eddy S Yang

Advisory Committee Members

James Bonner

Donald Buchsbaum

Jeffrey Engler

John Parant

Keshav Singh

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Breast cancer remains the most frequently diagnosed cancer amongst women worldwide. Despite advances in treatment, patients with more aggressive basal-like and HER2-positive cancer experience high rates of recurrence and necessitate novel therapeutic approaches. A class of inhibitors targeted against poly (ADP-ribose) polymerases (PARP), important DNA repair proteins, are effective in cancers with a defective DNA repair response. As such, extensive preclinical and clinical research has examined their efficacy in these cancers. Although this data is promising, it is only applicable to a lim-ited patient population. The main goal of this dissertation is to expand the utility of these well-tolerated drugs to a larger patient population, specifically DNA repair proficient cancers. We hy-pothesized transiently inducing a DNA repair deficiency in cancer cells would sensitize them to PARP inhibitors. Emerging evidence suggests epidermal growth factor receptor (EGFR) has effects outside of canonical signaling pathways, including regulation of DNA repair. Our data indicates inhibition of EGFR attenuates the DNA repair response and induces a contextual synthetic lethality in triple negative breast cancer cell lines and mouse models. Even though EGFR has been implicated in repair, little mechanistic in-formation is available. We determined EGFR might alter repair kinetics through novel interactions with important DNA repair proteins, BRCA1 and PARP1. The nuclear inter-action with PARP1 was enhanced with DNA damage and attenuated upon EGFR inhibi-tion. Importantly, this potential repair complex was observed bound to the DNA near sites of damage. Finally, we examined primary breast cancer specimens for their protein expression of two markers, thought important in our preclinical research, PARP1 and phospho-p65. These markers were overexpressed and directly correlated in HER2-positive, as compared to HER2-negative, breast cancers. Additional subtype analysis re-vealed PARP1 was overexpressed in both HER2-positive and basal-like breast cancers. Together the data in this dissertation provide evidence for a role of EGFR in DNA repair and indicate targeting of this receptor sensitizes DNA repair proficient cancers to PARP inhibitors. This novel therapeutic regimen may be of clinical value to patients with more aggressive subtypes of breast cancer, who might benefit from PARP1 and phospho-p65 biomarker selection in a clinical trial setting.

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