Abstract LB-018: Loss of function mutations of an ETS repressor expand the ETS positive subset of prostate cancer

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Abstract Recent genomic profiling of both primary and metastatic prostate cancers has revealed novel loss-of-function point mutations and copy number deletions of the gene ERF, an ETS transcriptional repressor with a nearly identical DNA-binding domain to the TMPRSS2-ERG oncogene product. Furthermore, ERF homozygous loss or point mutations occur exclusive of the ERG upregulation that occurs in 50% of prostate cancers following fusion of androgen-regulated upstream genomic elements of TMPRSS2 to the ERG gene. We characterized the function of ERF, as well as its relationship to ERG using CRISPR and shRNA technology to investigate both normal prostate- and patient tumor-derived organoid cultures, as well as existing TMPRSS2-ERG positive models. In both normal prostate and tumor models lacking upregulated ERG, inhibition of the ERF repressor leads to an expansion of the androgen transcriptome, and recapitulates phenotypic features seen with ERG upregulation. Cistromic analysis reveals that ERF occupies androgen-receptor (AR) associated chromatin, overlapping with potential ERG sites. Accordingly, in the presence of the upregulated ERG oncogene, ERF is now unable to bind any AR associated chromatin, and the AR transcriptome is expanded. CRISPR-mediated loss of ERG in TMPRSS2-ERG positive models leads to a halt of tumor cell growth, but concomitant loss of the ERF repressor partially restores cellular proliferation. We conclude that ERF is an endogenous repressor of androgen signaling in normal prostatic tissue and a potential tumor suppressor in prostate cancer. It occupies chromatin associated with AR-regulated genes and inhibits their transcriptional regulation. Loss of ERF function, either by mutation or more frequently by competition with the TMPRSS2-ERG gene product, leads to an expansion of the androgen transcriptome. Thereby, the ETS positive subtype of prostate cancer, currently defined by an activating ETS fusion event (e.g. TMPRSS2-ERG) should be expanded to encompass genomic loss of a repressive ETS factor. Citation Format: Rohit Bose, Wassim Abida, Wouter Karthaus, Joshua Armenia, Phillip Iaquinta, John Wongvipat, Michael Doran, Haley Hieronymus, Philip Watson, Patrick Sullivan, Yupu Liang, Nikolaus Schultz, Charles Sawyers. Loss of function mutations of an ETS repressor expand the ETS positive subset of prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-018.