Abstract 3240: A transgenic mouse model of a common genetic aberration in prostate cancer: Chromosomal rearrangement of TMPRSS2:ERG

Abstract

Abstract The most prevalent gene fusion identified in prostate cancer (PC) to date is the recurrent fusion of the 5’ region of Transmembrane Serine Protease 2 (TMPRSS2) to the transcription factor Ets related gene (ERG). The fusion occurs in ∼50% of PC and has been identified in malignant cells preceding the development of prostate adenocarcinoma. This has led to the hypothesis that the rearrangement is an early and critical event in PC. The purpose of this study is to generate a novel mouse model to investigate the role of the transgene in development of PC, and to examine the biological and molecular properties of prostate epithelial cells carrying a translocation of the ERG oncogene. The fusion is a result of deletion in the genomic region between TMPRSS2 and ERG, which are both located on chromosome 21. Several fusion variants have been described and the focus of this study is the TMPRSS2 exon 2 and ERG exon 4 variant which has been associated with aggressive disease. Importantly, expression of the fusion gene initiates from the TMPRSS2 promoter which is primarily expressed in the prostate and regulated by androgen receptor (AR), which is central to PC development. The objectives of this study included the generation of a novel model that maintains regulation and processing of the translocation. This was achieved by using the complete promoter region, including androgen regulatory regions, and the human genomic sequence thus maintaining the intron/exon arrangement and facilitating alternative splicing. Transgenic mice in the FVB and C57/BL6 background were produced using a 230 Kb construct generated by recombineering technology, where ∼25Kb of the TMPRSS2 promoter region and its first two exons were fused to the entire genomic ERG locus following exon 4. Two splice variants of the transgene have been identified in mouse prostates corresponding to the presence and absence of a 72bp exon, replicating the pattern in human PC, where this has been associated with aggressive disease. No distinct histological phenotypic change has been observed in the murine prostate of transgenic animals at six to twelve months. Towards the aim of determining the role of this fusion in PC - further in vitro and in vivo assays are currently in progress with the objectives of 1) determining the role of AR in regulation of the promoter and 2) investigating alterations in gene expression profiles in distinct cell populations of the prostate harboring the transgene. Additional crosses with other mice carrying mutations significant to prostate cancer, e.g. Nkx 3.1 and PTEN mice are being performed thus allowing the investigation of the phenotypic effect of this fusion when combined with other common genetic events. 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 3240.