ERG upregulation and related ETS transcription factors in prostate cancer (original) (raw)
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Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome
Oncogene, 2005
Transcription factors encoded by the ETS family of genes are central in integrating signals that regulate cell growth and differentiation, stress responses, and tumorigenesis. This study, analysing laser microdissected paired benign and malignant prostate epithelial cells from prostate cancer (CaP) patients (n ¼ 114; 228 specimen) by GeneChip and quantitative real-time RT-PCR, identifies ETS-related gene (ERG), a member of the ETS transcription factor family, as the most frequently overexpressed proto-oncogene in the transcriptome of malignant prostate epithelial cells. Combined quantitative expression analysis of ERG with two other genes commonly overexpressed in CaP, AMACR and DD3, revealed overexpression of at least one of these three genes in virtually all CaP specimen (54 of 55). Comprehensive evaluation of quantitative ERG1 expression with clinicopathological features also suggested that ERG1 expression level in prostate tumor cells relative to benign epithelial cells is indicator of disease-free survival after radical prostatectomy.
Immunohistochemical expression of ERG in the molecular epidemiology of fatal prostate cancer study
The Prostate, 2013
BACKGROUND. Gene fusions between the ERG transcription factor and the androgenregulated gene TMPRSS2 occur in a subset of prostate cancers and contribute to transformation of prostatic epithelial cells. Prior reports have used fluorescence in situ hybridization (FISH) or quantitative PCR (QPCR) to determine the presence of TMPRSS2-ERG fusions or ERG expression, respectively. Recently, several groups have reported on immunohistochemistry (IHC) to measure ERG expression, which is much more readily performed in clinical practice. However, the prior studies examining ERG expression by IHC had small sample sizes or they failed to clarify the association of ERG protein expression with important clinicopathological features or prostate cancer-specific mortality. Methods: To address these deficits, we evaluated ERG expression by IHC in 208 radical prostatectomy samples from the Kaiser Permanente Molecular Epidemiology of Fatal Prostate Cancer (MEFPC) study, a case-control study of prostate cancer-specific mortality. RESULTS. Nuclear ERG expression was seen in neoplastic prostate epithelia in 49 of the samples (23.7%). ERG expression in tumor cells was associated with higher tumor stage (OR ¼ 2.0, 95% confidence interval 1.0-4.0, P value ¼ 0.04). ERG immunoreactivity was positively associated with prostate cancer-specific mortality, although the confidence interval was wide (OR ¼ 1.9, 95% confidence interval 0.88-4.0, P value ¼ 0.10). CONCLUSIONS. Our results demonstrate that ERG protein expression is readily quantifiable with an existing commercial antibody. Evaluating ERG protein expression may improve our ability to identify the subset of more aggressive, invasive prostate cancers. Prostate # 2013 Wiley Periodicals, Inc.
Heterogenous expression of ERG oncoprotein in Malaysian men with adenocarcinoma of the prostate
The Malaysian journal of pathology, 2018
INTRODUCTION Prostate cancer is a heterogenous disease and the mechanisms that drive it to behave differently are not well understood. Tumour expression of the ERG oncogene occurs in the majority of patients with prostate cancer in Western studies. This is considered to be oncogenic as ERG acts as a transcription factor to regulate genes involved in tumour proliferation and invasion. In this study we investigated expression of ERG in Malaysian men with prostate cancer. METHODS Tissues were collected from 80 patients with clinically detected prostate cancer and treated with radical prostatectomy. Cases were tested for ERG by immunohistochemistry using the mouse monoclonal antibody EP111. All blocks on 48 cases were tested in order to determine the extent of heterogeneity of ERG expression within individual cases. ERG expression was analysed in relation to patient age, ethnicity and tumour stage and grade. RESULTS Forty-six percent of cases were ERG positive. There was no significant ...
ERG is specifically associated with ETS-2 and ETV-4, but not with ETS-1, in prostate cancer
International Journal of Molecular Medicine, 2012
The erythroblast transformation-specific (ETS) family of transcription factors plays important roles in both physiological and pathological conditions. Even though many studies have focused on single ETS factors within a single tissue and within the context of specific promoters, the functional impact of multiple ETS members present within a specific cell type has not yet been investigated, especially in prostate cancer (PCa). As the most prominent gene rearrangement in PCa leads to the overexpression of the ETS-related gene (ERG), the aim of this study was to investigate whether ERG is part of a complex integrated transcriptional network that involves other ETS factors. More specifically, as the ETS family consists of 27 members, we focused our efforts initially on investigating whether ERG is associated with the three family members, ETS-1, ETS-2 and ETS variant gene-4 (ETV-4), in PCa as a proof of principle.
Journal of Cancer, 2015
Background: Despite a growing number of studies evaluating cancer of prostate (CaP) specific gene alterations, oncogenic activation of the ETS Related Gene (ERG) by gene fusions remains the most validated cancer gene alteration in CaP. Prevalent gene fusions have been described between the ERG gene and promoter upstream sequences of androgen-inducible genes, predominantly TMPRSS2 (transmembrane protease serine 2). Despite the extensive evaluations of ERG genomic rearrangements, fusion transcripts and the ERG oncoprotein, the prognostic value of ERG remains to be better understood. Using gene expression dataset from matched prostate tumor and normal epithelial cells from an 80 GeneChip experiment examining 40 tumors and their matching normal pairs in 40 patients with known ERG status, we conducted a cancer signaling-focused functional analysis of prostatic carcinoma representing moderate and aggressive cancers stratified by ERG expression. Results: In the present study of matched pairs of laser capture microdissected normal epithelial cells and well-to-moderately differentiated tumor epithelial cells with known ERG gene expression status from 20 patients with localized prostate cancer, we have discovered novel ERG associated biochemical networks. Conclusions: Using causal network reconstruction methods, we have identified three major signaling pathways related to MAPK/PI3K cascade that may indeed contribute synergistically to the ERG dependent tumor development. Moreover, the key components of these pathways have potential as biomarkers and therapeutic target for ERG positive prostate tumors.
To study ERG expression in benign, pre-neoplastic, and neoplastic lesions of prostate
Asian journal of medical sciences, 2024
Background: Prostate cancer (PCa) is the second most common malignancy in men and the sixth leading cause of death. Clinical course of PCa is highly variable and current clinico pathological parameters are unable to predict accurately the course of the disease because of genetic heterogeneity seen in this tumor. Aims and Objectives: The aim of the study was to study the prevalence of E26 transformation-specific-related gene (ERG) expression in benign and malignant lesions of prostate in Northern Indian patients. Whether ERG expression using immunohistochemical (IHC) methods can also be used for differentiating various lesions of the prostate gland is also evaluated. Materials and Methods: This is an observational study conducted on 50 biopsy specimens encompassing different lesions of prostate. The study was carried out in the
Prognostic potential of ERG (ETS-related gene) expression in prostatic adenocarcinoma
International Urology and Nephrology, 2013
Purpose-Following patients after prostatectomy can be expensive and stressful, therefore, a novel and reliable approach to improve stratification is needed both at diagnosis of PCa and following its treatment. We evaluate the association of both ERG and claudin-4,-5 and betacatenin expression in tumor tissues of patients with organ confined and advanced prostatic adenocarcinomas. Methods-A total of 30 patients were included in the study. Nine men, who underwent radical prostatectomy for organ confined (pT2N0M0) cancer (OCC); 11 patients with clinically advanced cancer (CAC); and 11 controls with benign prostatic hypertrophy (BPH). Using immunohistochemistry applied to tissue microarrays, each group was evaluated for beta-catenin, claudin-4,-5 and ERG expression. Results-The expression of ERG was higher in the CAC group as compared to OCC and BPH (p = 0.7684, p = 0.0224, respectively). Among these patients, 5 from the CAC (45%) and 5 from the OCC group (56%) stained positively for ERG (p = 1.0). The mean staining score for those with ERG+ advanced cancer was greater than that for the ERG+ organ-confined cancer (p = 0.0209). ERG staining correlated with Gleason score (Pearson correlation: 0.498, p = 0.0051), but not with serum PSA level (Pearson correlation: 0.404, p = 0.1202). When analyzing outcome data high ERG expressing tumors have shown a significantly worse overall survival (p = 0.0084). Conclusions-Our results of presence or absence of claudin-4 and-5 and ERG staining intensities suggest their potential as prognostic factors for prostate cancer.
ERG Protein Expression Is of Limited Prognostic Value in Men with Localized Prostate Cancer
ISRN urology, 2013
Background. The prognostic significance of ERG expression in prostate cancer (PCA) has generated mixed results. We sought to investigate the prognostic significance of ERG expression in a localized cohort of men with PCA. Material and Methods. We investigated ERG protein expression in a cohort of 198 men with localized PCA. ERG expression was correlated with patients' clinical outcome and several pathological parameters, including Gleason score (GS), pathological stage, surgical margin, and extra-capsular extension. Results. ERG expression was detected in 86/198 (43.4%) patients exclusively in neoplastic epithelium. Overall, ERG mean expression intensity was 1.01 ± 1.27 versus 0.37 ± 0.83 in acinar PCA compared to foamy type PCA (P < 0.001). In HGPIN, ERG intensity levels were comparable to those in foamy type PCA (0.13 ± 0.56) but significantly lower than those in acinar PCA (P < 0.001). ERG expression was significantly associated with extra-prostatic extension and higher...
A 36-gene Signature Predicts Clinical Progression in a Subgroup of ERG-positive Prostate Cancers
European Urology, 2013
Background: The molecular basis of the clinical heterogeneity of prostate cancer (PCa) is not well understood. Objective: The purpose of our study was to identify and characterize genes in a clinically relevant gene expression signature in a subgroup of primary PCa positive for transmembrane protease, serine 2 (TMPRSS2)-v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG). Design, setting, and participants: We studied gene expression profiles by unsupervised hierarchical clustering in 48 primary PCas from patients with a long clinical follow-up. Results were correlated with clinical outcome and validated in an independent patient cohort. Selected genes from a defined classifier were tested in vitro for biologic properties. Intervention: Initial treatment of primary tumors was radical prostatectomy. Outcome measurements and statistical analysis: Associations between clinical and histopathologic variables were evaluated by the Pearson x 2 test, Mann-Whitney U test, or Kruskal-Wallis test, where appropriate. The log-rank test or Breslow method was used for statistical analysis of Kaplan-Meier survival curves. Results and limitations: Most tumors that overexpressed ERG clustered separately from other primary PCas. No differences in any clinical end points between ERG-positive and ERG-negative cancers were detected. Importantly, within the ERG-positive samples, two subgroups were identified, which differed significantly in prostate-specific antigen recurrence-free survival, and cancer-specific and overall survival. From our findings, we defined a gene expression classifier of 36 genes. In a second, completely independent tumor set, the classifier also distinguished ERG-positive subgroups with different clinical outcome. In both patient cohorts, the classifier was not predictive in ERG-negative tumors. Biologic processes regulated by genes in the classifier included cell adhesion and bone remodeling. Tumor growth factor-b signaling was indicated as the main differing signaling pathway between the two ERG subgroups. In vitro biologic assays of two selected genes from the classifier (inhibin, beta A [INHBA] and cadherin 11, type 2, OBcadherin (osteoblast) [CDH11]) supported a functional role in PCa progression. Possible multifocality and limited number of PCa samples can be limitations of the study. Conclusions: The classifier identified can contribute to prediction of tumor progression in ERG-positive primary prostate tumors and might be instrumental in therapy decisions.
Proceedings of the National Academy of Sciences, 2009
Chromosomal rearrangements involving erythroblast transformation specific (ETS) family transcription factors were recently defined as the most common genetic alterations in human prostate cancer. Despite their prevalence, it is unclear what quantitative role they play in either initiation or progression of the disease. Using a lentiviral transduction and dissociated cell prostate regeneration approach, we find that acutely increased expression of ETS proteins in adult murine prostate epithelial cells is sufficient to induce the formation of epithelial hyperplasia and focal prostatic intraepithelial neoplasia (PIN) lesions, but not progression to carcinoma. However, combined expression of ERG with additional genetic alternations associated with human prostate cancer can lead to aggressive disease. Although ERG overexpression does not cooperate with loss of the tumor suppressor p53, it does collaborate with alterations in PI3K signaling, such as Pten knockdown or AKT up-regulation, to produce a well-differentiated adenocarcinoma. Most striking is our finding that overexpression of androgen receptor (AR) does not give rise to any hyperplastic lesions, but when combined with high levels of ERG, it promotes the development of a more poorly differentiated, invasive adenocarcinoma. These findings suggest that in human prostate cancer, the most potent function of ETS gene fusions may be to synergize with alternative genetic events and provide different pathways for carcinoma production and invasive behavior. Our results provide direct evidence for selective cooperating events in ERG-induced prostate tumorigenesis and offer a rational basis for combined therapeutic interventions against multiple oncogenic pathways in prostate cancer.