Abstract 2871: Inhibition of Androgen Receptor-Mediated Expression of Prostate Derived Ets Transcription Factor (PDEF) Induces a Loss of Prostate Cancer Cell Differentiation

Abstract While inhibition of androgen signaling has shown to extend the lives of many patients, there is a growing concern in the field that androgen ablation may select for a more aggressive and lethal phenotype of prostate cancer. It has long been known that androgen receptor (AR) mediates growth and cellular differentiation. Therefore, inhibition of AR may stem cancer growth, but concurrently cause cells to de-differentiate and gain migratory and invasive properties. Prostate derived ets transcription factor (PDEF) is an AR target gene highly expressed in normal prostate tissue and has shown to be sufficient to mediate terminal epithelial cellular differentiation in the lung and colon. Previous studies in our lab have demonstrated, through retrospective IHC staining of FFPE radical prostatectomy specimens, loss of PDEF expression significantly associated with increased incidence and patients’ shorter metastatic free survival time with early stage prostate cancer. Furthermore, previous studies in the literature have detected the PDEF promoter sequence through AR ChIP-Sequencing and ChIP-on-ChIP experiments. We therefore studied the regulation of PDEF expression by AR as a potential mediator of prostate epithelial cellular differentiation. Our data indicated that anti-androgens, androgen starvation or AR shRNA was sufficient to abrogate PDEF protein and mRNA expression. Stable expression of AR shRNA or PDEF shRNA by lentiviral infection displayed a coordinate decrease in e-cadherin expression and an increase in vimentin expression, indicating a potential shift to a mesenchymal-like phenotype. This epithelial-to-mesenchymal transition was also observed in cells acutely treated with anti-androgens bicalutamide or finasteride. Together, these results demonstrate that androgen ablation therapy may directly drive cells to de-differentiate and gain migratory/invasive capabilities, and therefore should only be indicated for those patients with a very short life expectancy or co-existing morbidities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2871. doi:1538-7445.AM2012-2871