Abstract 4962: ERG expression levels in prostate tumors reflect functional status of the androgen receptor as a consequence of fusion of ERG with AR regulated gene promoters

Abstract

Abstract Background: Androgen dependent overexpression of the TMPRSS2:ERG fusion is the most prevalent chromosomal rearrangement in prostate cancer. During our recent evaluations of the ERG downstream transcriptional targets, we identified 15-Hydroxyprostaglandin Dehydrogenase gene (HPGD) in response to ERG knock-down. HPGD is an enzyme that catalyzes the oxidation of prostaglandins and lipoxins by converting them into inactive keto-metabolites, and physiologically antagonizes COX-2, a prostaglandin-synthesizing enzyme. HPGD also behaves as a tumor suppressor in many cancers as overexpression of HPGD resulted in marked inhibition of cell growth. The objective of this study was to evaluate potential connection between ERG overexpression and prostaglandin signaling. Experimental procedures: Small interference RNA (siRNA) oligo duplex was used to knock-down endogenous ERG and HPGD expressions. Western blot assay and Immunofluorescence was used to detect protein expressions. QT-PCR (normalized to GAPDH) was used for transcriptome analysis. GeneChip, Chromatin immunoprecipitation assays and cell proliferation assay were utilized for functional analysis. Results: ERG knock-down in VCaP prostate tumor cells results in overexpression of HPGD, down regulation of the prostaglandin E2 receptor 4 (EP4), and inhibition of prostaglandin E2 induced Urokinase Plasminogen Activator (uPA) expression and cell growth. Comparison of HPGD between TMPRSS2:ERG positive and negative prostate tumors revealed a trend towards decreased HPGD expression in fusion positive tumors. Conclusions: Taken together, these data suggest that ERG over-expression in CaP cells may positively influence prostaglandin mediated signaling. Funding sources: NIH Grants RO1 DK065977 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4962.