Endocrine disruptors: AR regulation and prostate cancer

Thomas Jefferson University, Philadelphia PA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Prostate cancer is the most frequently diagnosed cancer and second leading cause of cancer death in the United States. Androgen receptor (AR) activity is required for prostate cancer growth, and therapeutic regimens for prostatic adenocarcinoma (CaP) are directed toward ablation of AR activity. Despite the initial efficacy of these therapies, recurrent tumors ultimately arise wherein AR has been inappropriately re-activated. No effective treatment exists for recurrent tumors, which lead to patient death. As such, there is an urgent need to identify the comprehensive set of factors that contribute to AR re-activation and tumor recurrence. We have shown that selected endocrine disrupting compounds (EDCs) prevalent in the environment can impinge on the most common mutant of AR that arises during tumor progression (AR-T877A) to stimulate receptor activity and concomitant cellular proliferation. Our new data demonstrate that this action of EDCs has clinical consequence, wherein a known EDC (bisphenol) increased tumor growth and shortened the time to tumor recurrence. Moreover, we showed that several tumor-derived AR mutants gain sensitivity to selected EDCs. Thus, these findings strongly support the central hypothesis of the present proposal, wherein secondary mutations known to occur during tumor progression can sensitize cells to EDC activity, and through these mechanisms EDCs can significantly impact the response to prostate cancer therapy. Here, we delineated 3 specific aims which challenge this hypothesis by first discerning the molecular mechanisms by which EDCs impinge on mutant AR function (Aim 1), identifying the comprehensive cohort of secondary alterations that sensitize cells to EDC activity (Aim 2), and challenging the biological consequence of EDC exposure in the presence of these secondary alterations using new models of disease (Aim 3). Combined, it is our belief that this proposal rigorously addresses the molecular and biological significance of EDC exposure on prostate cancer management and outcome. Given the persistence of each studied EDC in the American population, these studies may have significant impact on understanding the factors that impinge upon prostate cancer growth. [unreadable] [unreadable] [unreadable]