Abstract 2065: TMEFF2 is a novel androgen receptor co-activator in prostate cancer cells

The goal of this study is to delineate the role of a novel androgen receptor (AR) coactivator in advanced prostate cancer (PCa). While great advances have been made in the ability to detect PCa, the disease remains the second leading cause of cancer related deaths in men. The AR is a steroid nuclear receptor that serves a central function in both normal prostate cell homeostasis and in PCa; in fact, the vast majority of PCa tumors require androgens for growth. This dependency has led to the development and use of androgen deprivation therapies (ADTs) for the treatment of PCa. ADT is initially a successful form of treatment for most PCa patients; however, the majority of patients eventually relapse with castration-resistant prostate cancer (CRPC), which is currently incurable. Because sustained AR activity under androgen depleted conditions is a major contributor to the development of CRPC, identifying molecular mechanisms that contribute to AR activity in CRPC is paramount for the development of successful therapies. Our lab has been studying the role of the transmembrane protein with epidermal-like growth factor domain and two follistatin domains 2 (TMEFF2) in PCa. While TMEFF2 gene expression is repressed by hypermethylation in multiple cancers, TMEFF2 is overexpressed in PCa and CRPC, suggesting that TMEFF2 may have a unique function in PCa. Importantly, TMEFF2 expression is activated by the androgen receptor (AR) at the level of transcription and translation, which may contribute to its overexpression in PCa. Our data presented here indicate that TMEFF2 functions in PCa cells as a coactivator of the AR. Using shRNA to stably knockdown TMEFF2 expression in androgen dependent PCa and CRPC cell lines, we demonstrate that TMEFF2 activates the basal and androgen-induced expression of multiple androgen responsive genes, including prostate-specific antigen (PSA), at the mRNA and protein level. Importantly, the knock-down of TMEFF2 does not alter AR protein levels, indicating that TMEFF2 influences AR activity. Additionally, by coimmunoprecipitation analysis, we demonstrate that TMEFF2 interacts with the AR, and western blot analyses with cellular fractionation samples indicate that TMEFF2 has the ability to translocate to the nucleus of PCa cells. Based on these results, we conclude that TMEFF2 is a novel AR coactivator in PCa. Future studies will focus on understanding the nature and biological effects of the interaction between TMEFF2 and the AR, and delineating the molecular mechanism through which TMEFF2 activates AR-mediated gene expression. Because sustained AR activity in androgen depleted conditions is a major contributor to CRPC relapse and PCa mortality, the TMEFF2-mediated AR activation mechanism may be clinically useful as a therapeutic target in CRPC. Citation Format: Joshua Corbin, Thomas Green, Maria J. Ruiz-Echevarria. TMEFF2 is a novel androgen receptor co-activator in prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2065. doi:10.1158/1538-7445.AM2015-2065