Chromosomal translocations involving the ERG locus are frequent events observed in human prostate cancer pathogenesis, however the biologic role of ERG aberrant expression is controversial. 1 Here we demonstrate that the aberrant expression of ERG is a progression event in prostate tumorigenesis. We find that prostate cancer specimens containing the TMPRSS2:ERG genetic rearrangement are significantly enriched for loss of the tumor suppressor PTEN. In concordance with these findings, over-expression of ERG in the transgenic mouse prostate promotes a marked acceleration and progression of HGPIN to prostatic adenocarcinoma in a Pten heterozygous background. In vitro over-expression of ERG promotes cell migration, a property necessary for tumorigenesis, without affecting proliferation. ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration are found up-regulated in the presence of ERG over-expression. Thus, ERG plays a distinct role in prostate cancer progression and cooperates with PTEN haploinsufficiency to promote progression of HGPIN to invasive adenocarcinoma.The first recurrent translocation event in prostate cancer was recently described in a seminal study. 1 It results in the translocation of an ETS transcription factor (ERG or ETV1) to the TMPRSS2 promoter region, which contains androgen responsive elements. 1 The TMPRSS:ERG genetic rearrangement is the most common and has been reported to occur in approximately 40% of primary prostate tumors and results in an aberrant androgen regulated expression of ERG. 1-3 Additionally, ETS family members ETV1, ETV4, and ETV5 have

PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tumor suppressor that antagonizes signaling through the phosphatidylinositol-3-kinase-Akt pathway. We have demonstrated that subtle decreases in PTEN abundance can have critical consequences for tumorigenesis. Here, we used a computational approach to identify miR-22, miR-25, and miR-302 as three PTEN-targeting microRNA (miRNA) families found within nine genomic loci. We showed that miR-22 and the miR-106b∼25 cluster are aberrantly overexpressed in human prostate cancer, correlate with abundance of the miRNA processing enzyme DICER, and potentiate cellular transformation both in vitro and in vivo. We demonstrated that the intronic miR-106b∼25 cluster cooperates with its host gene MCM7 in cellular transformation both in vitro and in vivo, so that the concomitant overexpression of MCM7 and the miRNA cluster triggers prostatic intraepithelial neoplasia in transgenic mice. Therefore, the MCM7 gene locus delivers two simultaneous oncogenic insults when amplified or overexpressed in human cancer. Thus, we have uncovered a protooncogenic miRNA-dependent network for PTEN regulation and defined the MCM7 locus as a critical factor in initiating prostate tumorigenesis.