A causal role for ERG in neoplastic transformation of prostate epithelium

Abstract

A significant proportion of human prostate cancers carry a chromosomal rearrangement resulting in the overexpression of the ETS transcription factor, ERG; however, the functional significance of this event is poorly understood. We report here that up-regulation of ERG transcript is sufficient for the initiation of prostate neoplasia. In agreement with measurements of ERG transcripts, we found that ERG protein is expressed in neoplastic human prostate epithelium. Overexpression of ERG in prostate cell lines increased cell invasion. Moreover, targeted expression of this transcript in vivo in luminal prostate epithelial cells of transgenic mice results in initiation of prostate neoplasia observed as the development of focal precancerous prostatic intraepithelial neoplasia (PIN). Similar to human cancers, luminal epithelial cells in these PIN lesions displace diminishing in numbers basal epithelial cells and establish direct contact with the stromal cell compartment. Loss of basal cells is considered to be one of the critical hallmarks of human prostate cancer; however, the mechanisms responsible for this event were unknown. We propose that up-regulation of ERG in human prostate cancer activates cell invasion programs that subsequently displace basal cells by neoplastic epithelium. Our data demonstrate that ERG plays an important causal role in the transformation of prostate epithelium and should be considered as a target for prevention or early therapeutic intervention.mouse models ͉ prostate cancer ͉ prostatic intrepithelial neoplasia (PIN) ͉ ETS family A n outlier identification approach for the analysis of transcript profiles recently identified recurrent chromosomal rearrangements in human prostate cancer (1). Fusion events joining the androgen-responsive TMPRSS2 gene and members of the erythroblastosis virus E26 oncogene (ETS) family result in the overexpression of a N-terminally truncated or full-length forms of the ERG transcription factor (⌬N-ERG and ERG). Subsequent studies have confirmed that TMPRSS2-ERG fusion is a common genetic event that occurs early in prostate carcinogenesis at the transition between benign and prostatic intraepithelial neoplasia (PIN) epithelium (2). This rearrangement has been correlated with tumor metastasis and negative patient outcome (3, 4). To determine the role of ERG overexpression in prostate carcinogenesis, we modeled this alteration in prostate epithelial cells in culture and in mouse prostate epithelium in vivo. We report that up-regulation of ERG activates prostate cell invasion and results in the displacement of prostate basal epithelium by the luminal cells and the development of PIN. Results ERG Expression Produces an Invasive Phenotype Mediated by SerineProtease Activity. Transcript profiling studies have demonstrated overexpression of the ERG transcription factor in the majority of human primary prostate cancers (5). To determine the presence, cell type specificity of expression, and intracellular localization of ERG protein we performed immunofluorescent staining...

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

“…Taken together, these data provide the first insight into the critical function of ERG in the growth of prostate tumor cells in cell culture and in mice. These data support recent transgenic mice studies showing that the overexpression of ETV1 (Tomlins et al, 2007) or ERG (Klezovitch et al, 2008;Tomlins et al, 2008) in mouse prostate may induce the features of early CaP and also provide important new insights into the therapeutic potential of the ERG knockdown in CaP cells.…”

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.…”

“…The first mouse models used a probasin promoter to overexpress ERG 49,50 and ETV1. 36 These models demonstrate the ability of the trans gene (i.e., ERG or ETV1) to develop early molecular changes referred to as mouse PIN.…”

Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG

“…Finally, morphogenic transformation of ERG-induced cells mediated by co-expression with WNT11 implicates a potential role for ERG-and WNT11-activating genetic programs that promote polarization and protrusions. This type of cellular response is a biological signal for cell migration and cell invasion by which these pathogenic mechanisms have already been proposed for ERG in prostate cancer (Klezovitch et al, 2008). Herein, these data collectively provide novel molecular components of ERG-directed cellular signals as a model for acute leukemia patients with high ERG expression and poor prognosis.…”

“…Three fusion proteins composed of ERG with TMPRSS2 (Tomlins et al, 2005;Klezovitch et al, 2008), EWS (Sorensen et al, 1994) or TLS (Kong et al, 1997) create oncogenic proteins. The most frequent chromosomal fusion in prostate cancer consists of the 5 0 -untranslated region of TMPRSS2 fused with 3 0 -end ERG.…”