Abstract 2965: ERG and ETV1 regulate a common transcriptional network in prostate cells but in an opposite fashion

Abstract

Chromosomal rearrangements involving ERG or ETV1 have been reported in >50% prostate cancer cases. It is presently unknown how ERG and ETV1 function leads to prostate tumorigenesis, and whether the factors play similar roles in this process. To address this, we focused on identification of their direct chromosomal targets relevant for prostate cancer initiation and progression. We also generated Tmprss2-ERG and Tmprss2-ETV1 knockin mouse models to interrogate the in vivo roles of these two most prevalent gene fusions. To investigate the transcriptional program regulated by ERG and ETV1, we performed siRNA silencing experiments in prostate cancer cells and overexpression studies in normal prostate immortalized cells. With the aid of a biotin-tagging approach, we also identified chromatin sites occupied by ERG and ETV1 in prostate cells. Cross-referencing ETV1 and ERG gene promoter binding to global expression profiling data permitted characterization of ERG and ETV1 -regulated programs in prostate cells. These combined transcriptional studies revealed that a common transcriptional network regulated by ERG and ETV1 but in an opposite fashion. Indeed, ETV1 enhanced the androgen receptor (AR) pathway, favoring tumor growth, while ERG showed a negative effect over the same pathway. Consistent with this, in the mouse models, ERG and ETV1 also exhibited differential regulation of common pathways: exogenous expression of ERG from the endogenous Tmprss2 promoter was much lower than that of ETV1, possibly due to a negative regulation of AR target genes (including Tmprss2) by ERG; however, transgenic overexpression of a mutated version of AR was able to break this negative regulation and significantly upregulated Tmprss2-ERG expression in vivo. In contrast, Tmprss2-ETV1 expression alone was able to upregulate expression of AR targets in vivo. Moreover, although ectopic expression of either ERG or ETV1 from the endogenous Tmprss2 locus alone in mouse prostate was insufficient to initiate prostate tumorigenesis in vivo, Tmprss2-ETV1 cooperated with Pten loss to enhance the prostate cancer phenotype, whereas Tmprss2-ERG failed to significantly affect the prostate phenotype induced by Pten-loss. Finally, analysis of patient data supported a differential outcome based on the presence of ERG or ETV1 fusions. In summary, we conclude that ERG and ETV1 play different roles in prostate tumorigenesis, and accordingly prostate cancers with ERG or ETV1 fusions should be considered different molecular subtypes. These findings have important implications for the development of targeted therapy for ERG- and ETV1-associated prostate cancers. 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 2965. doi:1538-7445.AM2012-2965