The Origins And Functional Consequences Of Ets Gene Fusions In Prostate Cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The purpose of this study is to unravel the cellular mechanisms underlying the oncogenic ETS gene fusions, which are a hallmark of prostate cancer development. Recurrent gene fusions involving the 5’untranslated region of the androgen-regulated gene TMPRSS2 and the ETS family genes are observed in a majority of prostate cancers. Among the ETS family gene fusions, the TMPRSS2-ERG fusions involving the 5’untranslated region of TMPRSS2 with the ERG gene are the most common and found in approximately 50% of prostate cancers. However, the origins and functional consequences of ETS gene fusions are not clear. Using dual color fluorescence in situ hybridization (FISH), we demonstrate that stimulation with dihydrotestosterone (DHT) induces proximity between TMPRSS2 and ERG genomic loci in LNCaP cells, which are androgen sensitive and lack the TMPRSS2-ERG gene fusions. This effect was dependent on androgen receptor (AR). Importantly, androgen did not induce proximity between the TMPRSS2 and ERG loci in DU145 human prostate cancer cells, which are androgen insensitive. Further, a combination of androgen signaling and genotoxic stress that induces DNA double strand breaks results in the formation of TMPRSS2-ERG gene fusions in LNCaP cells. Interestingly, we observe that the ERG protein formed as a result of gene fusion binds to the promoter of wild type ERG and activates its transcription. The VCaP cell line that endogenously harbors the TMPRSS2-ERG gene fusion has high levels of wild type ERG. Treatment with androgens induces the expression of both the TMPRSS2-ERG and wild type ERG transcripts in VCaP cells. Lenti virus mediated stable over expression of TMPRSS2-ERG in PC3 cells results in an increase in the expression levels of wild type ERG. This auto-activation of wild type ERG is observed in about 50% of clinically localized and 25% of metastatic prostate cancers harboring the TMPRSS2-ERG gene fusions, but not in ETS negative prostate cancers. Taken together, our studies provide a mechanistic framework for the up-regulation of ERG transcription in prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2155. doi:10.1158/1538-7445.AM2011-2155