Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate

Abstract

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

ETS rearrangements in prostate cancer

“…They further analyzed tumor samples demonstrating that 68% (27/ 40) of prostate cancers had loss of PTEN expression by immunohistochemistry in contrast to 38% (15/40) of cases with ERG rearrangement. 47 50 confirmed that these finding demonstrate that the overexpression of ERG is associated with tumor cell migration through a proteolytic molecular program. Recently, Carver et al 47 performed a series of studies to explore the concomitant relationship between TMRPSS2:ERG and the pten/PI3K/Akt pathways.…”

“…47 50 confirmed that these finding demonstrate that the overexpression of ERG is associated with tumor cell migration through a proteolytic molecular program. Recently, Carver et al 47 performed a series of studies to explore the concomitant relationship between TMRPSS2:ERG and the pten/PI3K/Akt pathways. Benign prostate cells (BPH-1) demonstrate increased proliferation with constitutively overexpressed Akt (AKT-1) as compared to controls.…”

“…There is now mounting molecular data for an important concomitant role of TMPRSS2:ERG and the pten/PI3K/ATK pathway activation in prostate cancer oncogenesis. The study from Carver et al 47 looked at data from human samples and determined that high-grade PIN demonstrates ERG gene rearrangement in 10% of cases, whereas loss of PTEN as determined by immunohistochemistry was observed in 45% of cases. Similar to previous observations by our group on high-grade PIN with ERG rearrangement, 16,17 the associated prostate cancer also demonstrated the same gene fusion status.…”

Potential for targeted therapy in prostate cancers with ERG abnormalities

“…[1][2][3][4][5][6] Most commonly, fusion of the transcriptional regulator gene ERG (ETSrelated gene) with TMPRSS2 is seen, present in half or more of prostate cancers, although other partner genes, such as ETV1, ETV4 and ETV5, may be involved in translocations. 1,2,7 Subsequent studies have found these gene fusions to appear early in prostate cancer development, 6 present in a subset of cases of prostatic intra-epithelial neoplasia and putative precursor lesions.…”

“…However, other genetic alterations appear to be contributory components of tumor development, such as loss of PTEN and activation of the PI3-kinase pathway, particularly in the setting of progression from an intraepithelial neoplasm to invasive adenocarcinoma. 2,4,12 Although abnormalities of ETS genes are sometimes found in tumors of other organs, ERG-TMPRSS2 fusion is not seen in common neoplasms of other sites, both epithelial and non-epithelial. 3 As such, these abnormalities have begun to demonstrate tremendous potential for broad applications in diagnosis, prognostication and treatment of prostate cancer.…”