TMPRSS2-ERG -specific transcriptional modulation is associated with prostate cancer biomarkers and TGF-β signaling

Abstract

BackgroundTMPRSS2-ERG gene fusions occur in about 50% of all prostate cancer cases and represent promising markers for molecular subtyping. Although TMPRSS2-ERG fusion seems to be a critical event in prostate cancer, the precise functional role in cancer development and progression is still unclear.MethodsWe studied large-scale gene expression profiles in 47 prostate tumor tissue samples and in 48 normal prostate tissue samples taken from the non-suspect area of clinical low-risk tumors using Affymetrix GeneChip Exon 1.0 ST microarrays.ResultsComparison of gene expression levels among TMPRSS2-ERG fusion-positive and negative tumors as well as benign samples demonstrated a distinct transcriptional program induced by the gene fusion event. Well-known biomarkers for prostate cancer detection like CRISP3 were found to be associated with the gene fusion status. WNT and TGF-β/BMP signaling pathways were significantly associated with genes upregulated in TMPRSS2-ERG fusion-positive tumors.ConclusionsThe TMPRSS2-ERG gene fusion results in the modulation of transcriptional patterns and cellular pathways with potential consequences for prostate cancer progression. Well-known biomarkers for prostate cancer detection were found to be associated with the gene fusion. Our results suggest that the fusion status should be considered in retrospective and future studies to assess biomarkers for prostate cancer detection, progression and targeted therapy.

Cysteine-rich secretory protein 3 overexpression is linked to a subset of PTEN-deleted ERG fusion-positive prostate cancers with early biochemical recurrence

“…Activation of ERG expression, mostly caused by TMPRSS2:ERG gene fusion, results in aberrant activation of different signaling cascades including upregulation of several metabolic enzymes, as well as extracellular/ transmembrane proteins involved in cell adhesion, matrix remodeling, and signal transduction. 13,[24][25][26] Our study identifies CRISP3 as another extracellular protein, which is strongly upregulated in ERG fusionpositive cancers. The functional role of CRISP3 in prostate cancer development and/or progression is unclear.…”

“…Finding this association Cysteine-rich secretory protein 3 in prostate cancer by two independent approaches for ERG fusion detection (immunohistochemistry/fluorescence in situ hybridization) largely excludes a false-positive association due to inefficient immunostaining in a subset of damaged non-reactive tissues. Earlier data derived from mRNA expression screening studies by Brase et al 13 and Ribeiro et al 8 had already indicated an association between ERG fusion and CRISP3 expression in prostate cancer. Activation of ERG expression, mostly caused by TMPRSS2:ERG gene fusion, results in aberrant activation of different signaling cascades including upregulation of several metabolic enzymes, as well as extracellular/ transmembrane proteins involved in cell adhesion, matrix remodeling, and signal transduction.…”

“…11,12 We and others recently identified a tight link of CRISP3 expression to positive ERG fusion status in RNA expression screening studies. 8,13 Associations of possible prognostic biomarkers with molecularly distinct tumor subtypes raise the question, whether their prognostic relevance may be limited to certain tumor subgroups. Such phenomenons could also explain the varying outcome of earlier studies involving relatively small patient sets.…”

ETS fusion genes in prostate cancer

“…Data obtained by Iljin et al (2006) indicated a role of the WNT pathway in ERG-associated prostate cancer and showed high expression of HDAC1 in ERG-overexpressing tumor samples. Also, activation of the transforming growth factor b (TGFb) pathway has been associated with ERG overexpression (Brase et al 2011). Although the data reported in different studies are variable, a consistent association with ERG overexpression, of more than ten genes, including CACNA1D, TDRD1, PLA2G7, and NCALD, has been found (Iljin et al 2006, Jhavar et al 2008, Taylor et al 2010, Brase et al 2011).…”

Genomic Predictors of Outcome in Prostate Cancer

“…In fusionpositive cases, upregulated genes were related to mismatch base repair and histone deacetylation, whereas genes involved in insulinlike growth factor (IGF) and Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling were downregulated [39]. In addition Brase et al showed the TMPRSS2-ERG gene fusion results in the modulation of certain transcriptional patterns and wellknown PCa biomarkers like CRISP3 and TDRD1 that were found to be associated with the gene fusions [40]. Karnes and coworkers did not detect a direct association between TMPRSS2:ERG fusion status and outcome, but classifying the cohort according to TMPRSS2:ERG fusion status had a significant impact on the predictive value of other investigated markers [41].…”