African American (AA) men develop highly aggressive prostate tumors and are twice as likely to die of this malignancy than men from other racial backgrounds. Advanced prostate cancer (PCa) is usually treated with androgen deprivation therapy and chemotherapy with taxane drugs. Unfortunately, death occurs once the cancer becomes metastatic and resistant to therapy. Recent studies demonstrate that glucocorticoid receptor (GR) signaling confers resistance to taxane chemotherapy; however, the underlying mechanisms have not been clearly established or studied in the context of health disparities. Glucocorticoids are concurrently administered to PCa patients to mitigate the side effects of therapy, but recent evidence suggests that they may also accelerate disease progression. This poses a serious problem for AA men, who have chronically elevated levels of endogenous glucocorticoids and amplified glucocorticoid signaling compared to European American (EA) men. These observations implicate glucocorticoid signaling as a potential contributor to PCa mortality disparities, and suggest that targeting GR may attenuate therapy resistance in PCa and reduce these disparities. The proposed studies are aimed at mechanistically linking elevated GR signaling with resistance to taxane chemotherapy in PCa, and targeting GR to reverse this resistance. Currently, there is a fundamental lack in our understanding of the impact of GR-induced chemotherapy resistance in the context of racial disparities in prostate cancer mortality. This is caused by critical barriers in the field that include lack of studies linking GR signaling to PCa therapy resistance in the context of health disparities, and limited understanding of molecular mechanisms underlying GR-induced chemotherapy resistance. This proposal addresses these critical barriers by exploring the novel overall hypothesis that GR signaling is enhanced in AA prostate tumors and promotes chemotherapy resistance by upregulating stress survival genes. The hypothesis is supported by preliminary data suggesting that GR signaling robustly induces the expression of the chemoresistance- associated proteins LEDGF/p75 and Clusterin in AA-derived cell lines. We will evaluate our overall hypothesis through two specific aims: Aim 1. Test the hypothesis that GR directly induces chemoresistance in PCa cells by upregulating stress survival proteins. This will be explored in mechanistic studies using AA and EA cellular and xenograft models of PCa. Aim 2. Test the hypothesis that GR signaling is elevated in AA men with PCa, leading to increased expression and circulation of stress survival proteins. This will be explored by examining the expression of GR in prostate tumor tissues from AA and EA patients, as well as the circulating levels of LEDGF/p75 and Clusterin in AA and EA men with and without PCa. These exploratory and innovative studies use a mechanistic approach to establish the role of GR signaling in promoting chemotherapy resist...