The Role of Glucocorticoid Signaling in Prostate Cancer Health Disparities
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.
Medical Physiology, Medical Sciences, Neoplasms, Race and Ethnicity, Social Work, Glucocorticoids -- Physiology; Prostatic Neoplasms; Prostate Cancer; African Americans, Glucocorticoid Signaling, Health Disparities
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