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.

Alterations of chromosome 8, including amplification at 8q24 harboring the C-MYC oncogene, have been noted as one of the most common chromosomal abnormalities in prostate cancer (CaP) progression. However, the frequency of C-MYC alterations in CaP has remained uncertain. A recent study, using a new anti-MYC antibody, described prevalent upregulation of nuclear C-MYC protein expression as an early oncogenic alteration in CaP. Further, we have recently reported regulation of C-MYC expression by ERG and a significant correlation between C-MYC overexpression and TMPRSS2-ERG fusion in early stage CaP. These emerging data suggest that increased C-MYC expression may be a critical and early oncogenic event driving CaP progression. In this study, we 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 laser capture micro-dissected tumor cells and matched benign epithelial cells in a radical prostatectomy cohort with long follow-up data available. On the basis of our results, we conclude that elevated C-MYC expression in primary prostate tumor is biologically relevant and may be a predictor of future biochemical recurrence.

Polymorphisms at 8q24 are robustly associated with prostate cancer risk. The risk variants are located in nonprotein coding regions and their mechanism has not been fully elucidated.To further dissect the function of this locus, we tested two hypotheses: (a) unannotated microRNAs (miRNA) are transcribed in the region, and (b) this region is a cis-acting enhancer. Using next generation sequencing, 8q24 risk regions were interrogated for known and novel miRNAs in histologically normal radical prostatectomy tissue. We also evaluated the association between the risk variants and transcript levels of multiple genes, focusing on the proto-oncogene, MYC. RNA expression was measured in histologically normal and tumor tissue from 280 prostatectomy specimens (from 234 European American and 46 African American patients), and paired germline DNA from each individual was genotyped for six 8q24 risk single nucleotide polymorphisms. No evidence was found for significant miRNA transcription within 8q24 prostate cancer risk loci. Likewise, no convincing association between RNA expression and risk allele status was detected in either histologically normal or tumor tissue. To our knowledge, this is one of the first and largest studies to directly assess miRNA in this region and to systematically measure MYC expression levels in prostate tissue in relation to inherited risk variants. These data will help to direct the future study of this risk locus. [Cancer Res 2009;69(13):5568-74]

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