African Americans (AA) with prostate cancer (PC) have twice the incidence and mortality than European Americans (EA) and any other ethnic groups, however, the mechanism/s linked to this health disparity is not understood. The uncontrolled androgen receptor (AR) signaling in PC cells increases tumor development which is controlled by androgen deprivation therapy (ADT) in patients. However, ADT selects for androgen- independence and recurrence of aggressive tumors in AA-men. Notably, AA-men with PC have significantly higher circulating estrogens than EA-men. Since adipose tissue is the major source of estrogens in men and since PC risk increases with age and obesity, there appears to be a crucial link between adiposity and estrogenic signaling in PC progression. Indeed, estrogenic signaling via the estrogen receptor-beta (ERP) is implicated in aggressive tumor growth and metastasis. Our combined suppressive subtractive hybridization (SSH) analysis and race-based cDNA microarrays, showed a selective up-regulation of both the ERa co- repressor, SAFB2 and the ERf3 isoform, in freshly microdissected PC specimen. In the AA-derived PC cell line MDA-PCa-2b, activation of estrogen-ERP signaling axis conferred AR transactivation and proliferative responses in PC cells, even in the absence of androgen. Furthermore, adipose stem cells (ADMSCs) from AA-men secreted estrogens in response to tumor-derived factors and increased PC cell growth both in vitro and in vivo. We therefore hypothesize that activation ofAR signaling by estrogen-ERP axis is pivotal to the progression of PC in AA-men despite androgen ablation therapy. Our hypothesis will be tested by the following specific aims: (1) to evaluate the clinical utility of SAFB2 and ERb expression levels as biomarkers and/or prognostic indicators of aggressive PC in African Americans. (2) To determine if the estrogen-ERp axis augments AR-mediated growth and metastasis in SAFB2-expressing PC cells in vitro. (3) To investigate in vitro whether local estrogen production by ADMSCs from AA-men contributes to ERp-dependent enhanced growth and metastasis of PC cells under ADC in vitro, and (4) To demonstrate that ERp activation by systemic and/or ADMSC-derived estrogens increases growth of PC tumors under ADC in vivo.
The discovery of alternate signaling pathways that may lead to androgen resistance and aggressive PC growth in AA-men, would be of crucial importance. A crucial role of estrogen-ERP signaling axis in PC progression and the contribution of adipose stem cell derived estrogens on growth and metastasis of PC cells, will provide new clues for understanding the disproportionate incidence and mortality due to PC in African American natients and will rifilineate novel theraneutic strategies that can be easily implemented.
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