Date of Award

January 2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Othman Ghribi

Abstract

The cholesterol metabolites known as oxysterols play an important role in maintaining cell homeostasis. They play vital roles in inflammation, cell growth, cell signaling, immunity, oxidative stress and aging. Following the discovery that the most abundant oxysterol, 27-hydroxycholesterol (27-OHC) is a Selective Estrogen Receptor Modulator (SERM), it has been implicated in hormonal cancers such as breast and uterine cancer. 27-OHC is a ligand of estrogen receptors (ER), a nuclear hormone receptor involved in cell growth and proliferation. The downstream events followed by 27-OHC-induced ER activation in the context of breast cancer is unknown. Also, the role of 27-OHC in prostate cancer is ill-defined given the involvement of ER in prostate cancer (PCa) and benign prostatic hyperplasia (BPH). Our studies delineate for the first time a potential cellular mechanism of action of 27-OHC in the context of ER+ breast cancer, whereby 27-OHC induced ER activation in ER+ MCF7 cells increases cell proliferation via perturbing the p53-MDM2 axis. We demonstrate that 27-OHC, through ER, exacerbated p53 inactivation via MDM2 resulting in an increase in cell proliferation in ER+ breast cancer cells. Next, we address the possibility of 27-OHC exacerbating prostate cancer cell proliferation. In the context of BPH and PCa, we show that 27-OHC not only increased cell proliferation in tumorigenic cell lines, LNCaP and PC3 but also in the non-tumorigenic cells, RWPE-1. We further demonstrate that 27-OHC- induced cell

proliferation in prostate cells is specifically through ERβ. Given the tissue dependent selective ER modulation of 27-OHC, our novel findings suggest that 27-OHC activates ER signaling in the prostate. Altogether, our findings elucidate and establish the novel role and cellular mechanism of action of the oxysterol 27-OHC in the context of breast and prostate cancer. In the interest of discovering new therapeutic avenues for breast and prostate cancers, our work may aid in the development of novel therapies that could mitigate/halt/alleviate the progression of ER+ breast cancers and prostate cancers.

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