Investigation of a frequently mutated transcriptional repressor in prostate cancer, in particular its role in modulating androgen signaling and its effects on TMPRSS2-ERG dependent tumor maintenance.

274 Background: Recent genomic profiling of primary and metastatic prostate cancers revealed up to 27% of tumors contain putative loss-of-function point mutations or copy number deletions within the gene ERF, an ETS transcriptional repressor with a remarkably similar DNA-binding domain to the TMPRSS2-ERG gene product. Methods: Bioinformatic analysis of 450 patient tumors was obtained from the TCGA and SU2C datasets. Transcriptomic and cistromic analysis was achieved by RNA-seq and ChIP-seq on VCaP cells, as well as patient-derived organoid cultures of both normal and neoplastic prostates. Gene expression was inhibited by CRISPR or shRNA technology. Results: ERF copy number deletions are associated with Gleason 8+ primary disease (p = 0.0369), and ERF mRNA level inversely correlates with androgen-driven transcription (p < 0.0001) in the absence of androgen receptor amplification. Transient inhibition of ERG expression in TMPRSS2-ERG+ cancer models leads to a contraction of the androgen transcriptome. On th...