Cellular mechanisms of androgen action and androgen-response gene EAF2 in prostate cancer

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PROJECT SUMMARY/ABSTRACT This application is for the R50 Research Specialist in the laboratory of Dr. Zhou Wang at the University of Pittsburgh. A critical need for protected stable positions for scientists who understand both the basic biology and clinical aspects of urologic diseases exists. Our goal is to fulfill this need by providing a protected position for Dr. Laura E. Pascal in pursuance of the successful completion of the current and future aims of Dr. Wang's NCI funded EAF2 grant. Dr. Wang's NCI R01 CA186780 grant, “Roles of EAF2 in androgen action in the prostate”, which is in its 20th year of funding, began in 1996 with the identification and characterization of androgen-responsive genes in the prostate and was just awarded a renewal in 2015. The original aims of the past grant were 1) to characterize the effect of U19/EAF2 knockout on prostate homeostasis; 2) to determine if U19/EAF2 knockout can induce prostate cancer in PTEN+/- mice; and 3) to determine the role of ELL2, a U19/EAF2 binding partner, in U19/EAF2 action in the prostate. The grant received MERIT status in 2011 and the updated aims were 1) to test the hypothesis that loss of U19/EAF2 does not affect undeveloped prostate naïve to androgens, 2) to continue characterization of ELL2 in U19/EAF2 action in the prostate, and 3) to determine whether, and to what extent, ELL2- and EAF2-downstream genes overlap in the prostate. The current aims are 1) to investigate EAF2 interaction with p53, 2) to determine the role of EAF2 and p53 in AR- regulated gene expression and cell proliferation, and 3) to determine the effect of concurrent loss of EAF2 and p53 on prostate carcinogenesis. Dr. Pascal is actively working on experiments from Aims 2 and 3 of this current grant and was involved in the successful completion of previous Aims. Dr. Pascal began working on ELL-associated factor 2 (EAF2), an androgen-responsive transcription elongation factor, in 2008 when she joined the Dr. Wang's lab as a post-doctoral fellow. Because of her significant contributions and success in the advancement of this project, she was appointed Research Assistant Professor in the Wang lab in 2011. Dr. Wang initially discovered EAF2 as an androgen-responsive gene, up-regulated gene 19 (U19). With the assistance of Dr. Pascal, Dr. Wang's lab has generated multiple recent observations that indicate a key role for EAF2 in androgen action and prostatic diseases. Dr. Pascal was integrally involved in the publication of several recent reports that suggest EAF2 downregulation may be associated with aggressiveness of prostate cancer. Since joining Dr. Wang's lab, she has co-authored 5 publications focused on EAF2 in the prostate and has become an expert on the EAF2 knockout mouse phenotype, murine prostate tumor models with combined loss of EAF2 and tumor suppressors PTEN and p53, as well as several prostate tumor xenografts. Additionally, she is providing support for Dr. Wang's collaboration with Dr. Paul Johnston in in vivo xenograft studies of the efficacy of novel small molecules developed to inhibit AR intracellular trafficking. We request funding for a period of 5 years, allowing us to continue to support Dr. Pascal and the completion of the EAF2 grant and the tumor xenograft studies and to meet her career goal of direct participation as well as mentoring and training of post-doctoral fellows, graduate students and technicians in this research.