Abstract

African-American men are more likely to develop aggressive prostate cancer (PCa) and die from the disease than other ethnic groups. Glucocorticoid signaling is a contributing biological factor to worse PCa prognosis, and is emerging as a key driver of PCa progression in the absence of androgens. The mechanism involves glucocorticoids binding to glucocorticoid receptor (GR) and bypassing the androgen receptor (AR) signaling pathway to activate AR-target genes that promote tumor aggressiveness and therapy-resistance. This is problematic as African-American men have hypersensitive GR signaling and chronically-elevated levels of glucocorticoids linked to cumulative stressful life events. To explore the role of glucocorticoid signaling in PCa health disparities, this dissertation used a racially diverse pre-clinical model to examine the effects of GR activation on the expression of stress oncoproteins linked to tumor aggressiveness and therapy-resistance, specifically Lens Epithelium-Derived Growth Factor p75 (LEDGF/p75) and Clusterin (CLU). Results revealed a robust pattern of GR-induced upregulation of LEDGF/p75 and CLU in African-American (AA) PCa cells compared to European-American (EA) PCa cells. We also detected increased GR transcript expression in AA PCa tissues, compared to EA tissues, using Oncomine microarray datasets. In addition, a trend towards elevated circulating LEDGF/p75 and CLU was observed in sera of AA patient samples. Taken together, these findings provide an initial framework for understanding the contribution of GR signaling to PCa health disparities.

LLU Discipline

Physiology

Department

Basic Sciences

School

School of Medicine

First Advisor

Casiano, Carlos A.

Second Advisor

Figueroa, Johnny D.

Third Advisor

Mata-Greenwood, Eugenia

Fourth Advisor

Montgomery, Susanne B.

Fifth Advisor

Wilson, Colwick

Sixth Advisor

Zhang, lubo

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2018

Date (Title Page)

6-2018

Language

English

Library of Congress/MESH Subject Headings

Glucocorticoids -- Physiology; Prostatic Neoplasms; Prostate Cancer; African Americans

Subject - Local

Glucocorticoid Signaling; Health Disparities

Type

Dissertation

Page Count

216

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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