TMPRSS2-ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation

Abstract

The high prevalence of TMPRSS2-ERG rearrangements (B60%) in prostate cancer (CaP) leads to androgenic induction of the ETS-related gene (ERG ) expression. However, the biological functions of ERG overexpression in CaP remain to be understood. ERG knockdown in TMPRSS2-ERG expressing CaP cells induced striking morphological changes and inhibited cell growth both in cell culture and SCID mice. Evaluation of the transcriptome and specific gene promoters in ERG siRNA-treated cells and investigation of gene expression signatures of human prostate tumors revealed ERG-mediated activation of C-MYC oncogene and the repression of prostate epithelial differentiation genes (PSA and SLC45A3/ Prostein). Taken together, these data combining cell culture and animal models and human prostate tumors reveal that ERG overexpression in prostate tumor cells may contribute to the neoplastic process by activating C-MYC and by abrogating prostate epithelial differentiation as indicated by prostate epithelial specific markers.

Overexpression of C-MYC oncogene in prostate cancer predicts biochemical recurrence

“…7,19 Our laboratory has recently reported that TMPRSS2-ERG fusion, a common genomic alteration in CaP, activates C-MYC and abrogates prostate epithelial differentiation, suggesting a potential mechanism for the early C-MYC overexpression in a significant subset of CaP. 24 Indeed, in a cohort of well/moderately differentiated prostate tumors, in which other confounding genomic alterations may be minimal, we did find a highly significant correlation of ERG and C-MYC expression. 24 In this study, we further assessed whether C-MYC mRNA overexpression in primary prostate tumors was predictive of more aggressive tumor or disease progression.…”

“…24 Indeed, in a cohort of well/moderately differentiated prostate tumors, in which other confounding genomic alterations may be minimal, we did find a highly significant correlation of ERG and C-MYC expression. 24 In this study, we further assessed whether C-MYC mRNA overexpression in primary prostate tumors was predictive of more aggressive tumor or disease progression. Our approach was to quantitatively determine C-MYC mRNA expression levels in micro-dissected tumor cells and matched benign epithelial cells in a radical prostatectomy cohort with long follow-up data available.…”

Prostate cancer genes associated with TMPRSS2–ERG gene fusion and prognostic of biochemical recurrence in multiple cohorts

“…Although TMPRSS2 -ERG fusion has typically been reported as prevalent in 40 -50% of prostate tumours, the range has varied by as much as 25 -60% (Nam et al, 2007;Setlur et al, 2008;Sun et al, 2008;Yoshimoto et al, 2008;Hofer et al, 2009;Mosquera et al, 2009). The techniques used for TMPRSS2 -ERG detection, novel potential fusion products and genetic differences in population cohorts may account for these discrepancies.…”

Abnormal Expression of the ERG Transcription Factor in Prostate Cancer Cells Activates Osteopontin

“…Consensus ERG binding site mutations corresponding to nt À121 to À114 (5 0 -GGAGGAAG-3 0 to 5 0 -GGTAAAAG-3 0 ) and to nt À112 to À106 (5 0 -GTAG-GAG-3 0 to 5 0 -GTCGGAG-3 0 ) were constructed using the OPN-136/þ77 luciferase wild-type fragment as the template. Oligonucleotides encoding for small hairpin RNAs (shRNA) against ERG mRNA [targeted sequence described in (32)] was synthesized with appropriate loop and cohesive ends sequences according to the plasmid provider instructions and was cloned into pSilencer 2.1-U6 (Ambion Inc). All constructs were verified by sequencing (Genoscreen) and restriction enzyme digestion.…”