Abstract B23: Identification of TMPRSS2:ERG-dependent regulators of AR function and differentiation status in prostate cancer

Abstract

Abstract Oncogenic translocations involve the chromosomal rearrangement and fusion of two genes, which can result in either deregulated gene expression or the generation of a chimeric protein with unique oncogenic properties. Among these, fusions of the androgen-activated gene TMPRSS2 to the ETS transcription factor ERG occur in 40%–80% of prostate cancers and result in elevated expression of the ERG gene. Although a number of studies demonstrate the importance of ERG as a driver for prostate cancer development, the molecular mechanisms of ERG-mediated oncogenesis remain elusive. A deeper understanding of how ERG disrupts normal prostate biology may ultimately assist in the development of therapies that selectively target TMPRSS2:ERG -positive prostate cancer. We provide evidence that a primary role of ERG in prostate cancer is to specifically disrupt the normal regulation of androgen receptor (AR) signaling, resulting in a selective attenuation of AR's ability to promote prostate epithelial cell differentiation. We are testing the hypothesis that ERG proteins require recruitment of additional cofactors to mediate these AR regulatory functions, and that some of these protein partners may be valid therapeutic targets. Towards this end, we are working to elucidate the full network of ERG-interacting proteins, and validating which of these interactors are necessary and/or sufficient for the oncogenic and de-differentiation functions of ERG in prostate cancer. Citation Format: Zineb Mounir, Raymond Pagliarini, Fallon Lin, Markus Schirle, Justin Klekota, Yan Feng, Anke Hartung, Aron Jaffe, Gilles Buchwalter, Myles Brown. Identification of TMPRSS2:ERG-dependent regulators of AR function and differentiation status in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B23.