Estrogen receptor (ER) alpha-mediated regulation of the p53-targets MDM4, MDM2 and NOXA in human breast cancer
Swetzig, Wendy M.
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In this dissertation, I present the results of my investigation of the ability of ERα/ESR1 to regulate the p53-regulated proteins MDM2, MDM4 and NOXA/PMAIP1 in human breast cancer, and I discuss these findings in the context of related studies from the field. In Chapter 1, I present an overview of the literature and cover the following topics: breast anatomy and physiology; breast cancer diagnosis and treatment; the molecular functions of ERα, p53, MDM2, MDM4, and NOXA as they relate to tumor cell biology; recent progress in the field linking ERα and p53 signaling pathways to one another in breast cancer cells; and the objectives of my dissertation research. Chapter 2 focuses on crosstalk between ERα, MDM2 and MDM4 in breast cancer. In Chapter 2, I present my research findings on (1) the ability of ERα to regulate MDM2 and MDM4 expression in a p53-independent manner, using primary breast tumor samples, human breast cancer cell lines, and publicly available “omics” datasets as model systems; (2) the ability of MDM2/MDM4 to form a protein complex with ERα and to negatively regulate ERα expression, thereby establishing a negative feedback loop between ERα and MDM2/MDM4; and (3) the clinical relevance of the above-mentioned findings, by assessing the utility of total MDM2 and MDM4 gene expression in primary breast tumors as biomarkers predictive of patient outcome. Chapter 3 focuses on crosstalk between ERα and NOXA in breast cancer. In Chapter 3, I present my research findings on (1) the ability of ERα to regulate NOXA expression via p53-independent mechanisms using human MCF7 breast cancer cells and publicly available “omics” datasets as model systems; and (2) the physiological relevance of ERα-mediated regulation of NOXA expression by studying the function of NOXA in terms of cell cycle and apoptosis in MCF7 breast cancer cells. In Chapter 4, I discuss the translational implications of my research findings, as they relate to the field of breast cancer. I also propose future studies to further delineate signaling cross-talk between ERα, MDM2, MDM4, and NOXA.