Rearrangement of the ETS genes ETV-1, ETV-4, ETV-5, and ELK-4 is a clonal event during prostate cancer progression

Shaikhibrahim, Zaki; Braun, Martin; Nikolov, P; Boehm, Diana; Scheble, Veit; Menon, Roopika; Fend, Falko; Kristiansen, Glen; Perner, Sven; Wernert, Nicolas

doi:10.1016/j.humpath.2012.01.018

Cited by 16 publications

(15 citation statements)

References 36 publications

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“…The association of ERG with ETS-2 based on our findings is supported by a previous study reporting that ERG interacts with ETS-2 in vivo using the two-hybrid system (26). Our finding that ERG is associated with ETV-4 is highly intriguing, as ETV-4 is known to be rearranged in PCa, similar to ERG (2–4,39), combined with a recent report showing the occurrence of multiple ETS rearrangements within one prostate gland, within the same tumor focus and within the same nucleus (27), which may imply a potential cooperation or interaction between rearranged ETS genes in PCa.…”

Section: Discussionsupporting

confidence: 51%

“…ETV-4 on the other hand, was chosen as ETV-4 is known to be rearranged in PCa, similar to ERG (2–4), combined with a report showing the occurrence of multiple ETS rearrangements within one prostate gland, within the same tumor focus and within the same nucleus (27). Moreover, we recently reported the ETV-4 rearranged gene status in primary PCas and their corresponding lymph nodes, and found the rearrangement in 6% of both primary PCas and the corresponding lymph node metastases (39). Furthermore, ETV-4 has been shown to be required for anchorage-independent growth and cell proliferation gene expression program in PCa cell lines (40).…”

Section: Discussionmentioning

confidence: 99%

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ERG is specifically associated with ETS-2 and ETV-4, but not with ETS-1, in prostate cancer

Shaikhibrahim

Ochsenfahrt

Fuchs

et al. 2012

International Journal of Molecular Medicine

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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. Using western blot analysis, we show that ERG, ETS-1, ETS-2 and ETV-4 are expressed in PC3 cell nuclear extracts and in protein lysates prepared from human PCa prostatectomy specimens. Immunoprecipitations using an anti-ERG antibody were used with PC3 cell nuclear extracts as well as with a pooled protein lysate sample prepared from the PCa tissue samples of five patients. Importantly, our results revealed that ERG is specifically associated with ETS-2 and ETV-4, but not with ETS-1, in PC3 cell nuclear extracts and PCa tissue protein lysates. Our findings strongly support the notion that ERG is part of a complex integrated transcriptional network that involves other ETS factors, which are likely to cooperate or influence the activity of ERG in PCa. The functional impact of multiple ETS factors being associated with ERG in PCa requires further study, as it may provide insights into the mechanism by which ERG exerts its influence in PCa and may subsequently contribute to our understanding of the molecular basis of PCa.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

ERG is specifically associated with ETS-2 and ETV-4, but not with ETS-1, in prostate cancer

Shaikhibrahim

Ochsenfahrt

Fuchs

et al. 2012

International Journal of Molecular Medicine

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“…However, the frequency of gene fusions and overexpression of these ETS proteins is very low compared with ERG overexpression. 28, 29 …”

Section: Discussionmentioning

confidence: 99%

Distinct ERG rearrangement prevalence in prostate cancer: higher frequency in young age and in low PSA prostate cancer

Schaefer

Ramoner

et al. 2013

Prostate Cancer Prostatic Dis

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Background:The TMPRSS2-ERG gene fusion resulting in ERG overexpression has been found in around 50% of prostate cancers (PCa) and is a very early event in tumorigenesis. Most studies have reported on selected surgical cohorts with inconsistent results. We hypothesized that ERG gene rearrangements impact tumor development and investigated the frequency of ERG overexpression in the context of clinicopathological tumor characteristics.Methods:ERG overexpression (ERG+ or ERG-) was determined by immunohistochemistry (IHC) in 1039 radical prostatectomy (RP) tumors and association with PSA, D'Amico risk score, histopathology, biochemical recurrence, body mass index and age of PCa cases was analyzed.Results:ERG+ was associated with younger age at diagnosis (P<0.0001), lower serum PSA (P=0.002) and lower prostate volume (PV) (P=0.001). It was most frequent in the youngest age quartile (⩽55 years, 63.9% ERG+) and decreased constantly with increasing age to 40.8% in the oldest age quartile (⩾67 years, P<0.0001). In the PSA range <4 ng ml−1 the frequency of ERG positivity was 60.2% compared with 47.5 and 49.1% in the PSA ranges 4–10 and ⩾10 ng ml−1, respectively. In the first age quartile, ERG+ patients had lower median serum PSA and fPSA% and smaller PV. In the highest age quartile tumor volume (TV) was increased. Similar differences were observed in the low PSA range. Multivariate analysis identified the first age quartile as a predictor for ERG status (odds ratios (OR) 2.05, P=0.007). No association was found with the D'Amico progression risk score and with biochemical tumor recurrence.Conclusions:ERG+ tumors manifest clinically at lower PSA levels and their prevalence is age dependent. This suggests acceleration of tumor development by ERG overexpression that results in earlier tumor detection in young patients. Long-term results are warranted to determine the impact of ERG overexpression on disease outcome.

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“…In contrast with ERG and FLI1, which promote transcriptional activation of ETS binding site‐containing reporter genes through large N‐terminal domains, FEV lacks this N‐terminal domain but has a C‐terminal domain rich in alanine residues, a feature common to various transcription repressors. FEV may thus act as a transcriptional repressor of the ERG subfamily, with expression restricted to the enterochromaffin (EC) serotonin cell‐based system of the brain and intestine, promoting NE differentiation via homeodomain transcription factor Nkx2.2 activation, and to human prostate tissue, where it is expressed differentially in the stroma and glands of the peripheral zone . As none of the ileal carcinoids we examined showed FEV translocation, we speculate that FEV , one of the most infrequently rearranged genes in the ETS family, could be responsible for the development from common ancestors of either ileal ES or EC/serotonin‐differentiated NE tumours, possibly through gene translocation in FEV ‐related ileal ES, or FEV overexpression in ileal NE tumours .…”

Section: Discussionmentioning

confidence: 98%

Ewing sarcoma of the small bowel: a study of seven cases, including one with the uncommonly reported EWSR1–FEV translocation

et al. 2014

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Rearrangement of the ETS genes ETV-1, ETV-4, ETV-5, and ELK-4 is a clonal event during prostate cancer progression

Cited by 16 publications

References 36 publications

ERG is specifically associated with ETS-2 and ETV-4, but not with ETS-1, in prostate cancer

ERG is specifically associated with ETS-2 and ETV-4, but not with ETS-1, in prostate cancer

Distinct ERG rearrangement prevalence in prostate cancer: higher frequency in young age and in low PSA prostate cancer

Ewing sarcoma of the small bowel: a study of seven cases, including one with the uncommonly reported EWSR1–FEV translocation

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