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...

Background: Expression levels of mRNA and protein by cell types exhibit a range of correlations for different genes. In this study, we compared levels of mRNA abundance for several cluster designation (CD) genes determined by gene arrays using magnetic sorted and laser-capture microdissected human prostate cells with levels of expression of the respective CD proteins determined by immunohistochemical staining in the major cell types of the prostate -basal epithelial, luminal epithelial, stromal fibromuscular, and endothelial -and for prostate precursor/ stem cells and prostate carcinoma cells. Immunohistochemical stains of prostate tissues from more than 50 patients were scored for informative CD antigen expression and compared with cell-type specific transcriptomes.

The identity of Na+/H+ exchanger (NHE) isoforms in the human small intestine and colon and their role in vectorial Na+ absorption are not known. The present studies were undertaken to examine the regional and vertical axis distribution of NHE-1, NHE-2, and NHE-3 mRNA in the human intestine. Ribonuclease protection assays were used to quantitate the levels of mRNA of these isoforms in various regions of the human intestine. In situ hybridization technique was used to localize NHE-2 and NHE-3 mRNA in the colon. The NHE-1 isoform message was present uniformly throughout the length of the human intestine. In contrast, mRNA levels for human NHE-2 and NHE-3 isoforms demonstrated significant regional differences. The NHE-3 abundance was found in decreasing order: ileum > jejunum > proximal colon = distal colon. The NHE-2 message level in the distal colon was significantly higher than in the proximal colon but was evenly distributed in the small intestine. In addition, NHE-2 mRNA was present in surface epithelial cells as well as in cells of the crypt region, suggesting the presence of NHE-2 message throughout the vertical axis of the colonic crypts. In contrast, NHE-3 mRNA was localized to surface colonocytes in the proximal colon. On the basis of this tissue-specific localization of NHE-2 and NHE-3 mRNA, it can be speculated that the relative contribution of NHE-2 and NHE-3 isoforms in Na+ absorption in the human intestine may be region specific, and these putative apical isoforms may be differentially regulated.

Purpose-Collecting duct renal cell carcinoma (CDRCC) is a rare entity. Recent surgical series on CDRCC presented conflicting results. In this study, we use a United States population-based dataset to describe the survival experience of patients with CRDCC to those with clear cell renal cell carcinomas (CCRCC).Materials and Methods-Cases of CDRCC and CCRCC were identified from the SEER Program (2001Program ( -2005. Demographic and pathologic characteristics at time of diagnosis were compared. Differences in disease-specific survival were compared with univariate and multivariate Cox regression analysis.Results-A total of 160 cases of CDRCC were present in the SEER database from 2001-2005. Over that time period, 33,252 CCRCC cases were diagnosed. CDRCC was more common in AfricanAmericans vs. Caucasians (23% vs. 9%, p<0.001). CDRCC were more commonly T3+ vs. T2/T1 (33% vs. 18%, p<0.001) and metastatic vs. regional/local (28% vs. 17%, p=0.001). Nephrectomy rates were similar (84% and 78%, p=0.06). The 3-year disease-specific survival (DSS) rates were 58% for CDRCC and 79% for CCRCC. In multivariate analysis, there was an increased mortality risk for patients with CDRCC compared to CCRCC (HR 2.42, 95% CI 1.72 -3.39, p = 0.001).Conclusions-Compared to CCRCC, patients with CDRCC present at higher stage and more often occurs in African-Americans. Even after adjusting for demographic, surgical and pathologic factors, the DSS is significantly worse for those with CDRCC compared to CCRCC. Further research into the biology of this rare tumor is required to explain these results.