Abstract B28: TMPRSS2- driven ERG in primary prostate epithelium demonstrates castration-resistant expression and expands a unique population of progenitor cells

Abstract It has become increasingly appreciated that recurrent genomic rearrangements contribute to the genesis of solid tumors. The genomic rearrangement of the Ets transcription factor, Ets related gene (ERG), with the promoter of the highly expressed Transmembrane protease serine 2 (TMPRSS2) gene, has been demonstrated in 20-65% of prostate adenocarcinoma precursor lesions, implying that ERG may contribute a function selected early in cancer formation. However, the functional role of ERG in developing prostate cancer is unclear. This study utilized bacterial artificial chromosome transgenesis, to produce a mouse model that recapitulates the genetic regulatory features of the genomic TMPRSS2-ERG translocation, where exon 1 and 2 of TMPRSS2 is fused to the region downstream of ERG exon 8. This model allows mechanistic investigations into the function and regulation of expression for TMPRSS2 promoter-driven ERG in the earliest initiating phase of tumorigenesis. Using QRT-PCR, TMPRSS2-ERG was expressed in the progenitor containing, Sca-1hi fraction of FACS-separated primary prostate cells. In addition, the fusion gene functioned to expand a unique subpopulation of prostate epithelial progenitors when compared to wild type, as demonstrated by serially passaged in vitro sphere forming assays. Androgen regulation of TMPRSS2 has been shown in a limited number of androgen receptor positive luminal prostate cancer cell lines. In this study, TMPRSS2-ERG expression demonstrated a significant castration-resistant component, suggesting mechanisms of AR-independent transcriptional regulation for the TMPRSS2 promoter in the setting of primary prostate epithelial cells. Introduction of the TMPRSS2-ERG fusion alone did not result in histological change, where prostate sections from mice up to 15 months of age were examined. However, the functionality of the model was shown as TMPRSS2-ERG synergized with heterozygous Pten loss to promote PIN. No apparent genetic interaction was observed between TMPRSS2-ERG and Nkx3.1 loss. These studies demonstrate the potential for androgen independent TMPRSS2-ERG expression in primary prostate epithelium and show that TMPRSS2-ERG expression promotes increased self-renewal of prostate progenitors. These data support a model whereby TMPRSS2-ERG regulates progenitor cell de-differentiation or survival, including within a population of castration-resistant progenitors. Citation Format: Orla M. Casey, Paul G. Hynes, Lei Fang, Wassim G. Abou-Kheir, Philip L. Martin, Heather S. Tillman, Hibah O. Awwad, Luhua Zhang, Kathleen Kelly. TMPRSS2- driven ERG in primary prostate epithelium demonstrates castration-resistant expression and expands a unique population of progenitor cells [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 B28.