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Peter Birner - One of the best experts on this subject based on the ideXlab platform.
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MAP kinase activity supported by BRAF ^ V600E mutation rather than gene amplification is associated with ETV1 expression in melanoma brain metastases
Archives of Dermatological Research, 2014Co-Authors: Peter Birner, Sebastian F Schoppmann, Anna S. Berghoff, Carina Dinhof, Christine Pirker, David Capper, Peter Petzelbauer, Andreas Deimling, Walter Berger, Matthias PreusserAbstract:In primary melanoma, ETV1 transcription factor was suggested to be activated mainly by gene amplification and to promote tumor growth in cooperation with BRAF ^ V600E . Aim of this study was to investigate ETV1 expression in human melanoma with a focus on brain metastases. We investigated ETV1 in 68 human melanoma brain metastases using FISH for ETV1 gene (located at chromosome 7p21) and centromere chromosome 7 and immunohistochemistry for ETV1, BRAF ^ V600E , and ETV1/BRAF associated proteins pMSK1, pRSK1, pp38, pMEK1/2, MAPKAP kinase 2, CIC, HIF-1alpha and Ki-67. We further studied ETV1 copy number variations in 32 melanoma cell lines from primary and metastatic lesions using array CGH. The influence of the MAP kinase pathway activity on ETV1 mRNA and protein expression under BRAF wild-type and BRAF ^ V600E conditions were determined in melanoma cell lines using qRT-PCR and Western Blot. No ETV1 high grade amplifications were observed in tissue samples, but low grade ETV1 gene amplifications were found in 7 (10.3 %) melanoma brain metastases. ETV1 protein expression in tissue samples (15 %) correlated with BRAF ^ V600E status ( p = 0.007) and HIF-1alpha expression ( p = 0.049), but not with ETV1 gene dose. Application of the BRAF^V600E-specific inhibitor vemurafenib and the BRAF^V6ooE/V600K-inhibitor dabrafenib revealed predominant regulation of ETV-1 mRNA and protein via MAPK-pathway. ETV1 expression is a rare event in human melanoma and seems to be rather based on hyperactivation of MAPK signals, by BRAF ^ V600E mutation, than on ETV1 gene amplification. Consequently, therapeutic inhibition of BRAF and the downstream MAPK pathway also down-regulates oncogenic ETV1 expression.
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map kinase activity supported by braf v600e mutation rather than gene amplification is associated with ETV1 expression in melanoma brain metastases
Archives of Dermatological Research, 2014Co-Authors: Peter Birner, Sebastian F Schoppmann, Anna S. Berghoff, Carina Dinhof, Christine Pirker, David Capper, Peter Petzelbauer, Andreas Deimling, Walter Berger, Matthias PreusserAbstract:In primary melanoma, ETV1 transcription factor was suggested to be activated mainly by gene amplification and to promote tumor growth in cooperation with BRAF V600E . Aim of this study was to investigate ETV1 expression in human melanoma with a focus on brain metastases. We investigated ETV1 in 68 human melanoma brain metastases using FISH for ETV1 gene (located at chromosome 7p21) and centromere chromosome 7 and immunohistochemistry for ETV1, BRAF V600E , and ETV1/BRAF associated proteins pMSK1, pRSK1, pp38, pMEK1/2, MAPKAP kinase 2, CIC, HIF-1alpha and Ki-67. We further studied ETV1 copy number variations in 32 melanoma cell lines from primary and metastatic lesions using array CGH. The influence of the MAP kinase pathway activity on ETV1 mRNA and protein expression under BRAF wild-type and BRAF V600E conditions were determined in melanoma cell lines using qRT-PCR and Western Blot. No ETV1 high grade amplifications were observed in tissue samples, but low grade ETV1 gene amplifications were found in 7 (10.3 %) melanoma brain metastases. ETV1 protein expression in tissue samples (15 %) correlated with BRAF V600E status (p = 0.007) and HIF-1alpha expression (p = 0.049), but not with ETV1 gene dose. Application of the BRAFV600E-specific inhibitor vemurafenib and the BRAFV6ooE/V600K-inhibitor dabrafenib revealed predominant regulation of ETV-1 mRNA and protein via MAPK-pathway. ETV1 expression is a rare event in human melanoma and seems to be rather based on hyperactivation of MAPK signals, by BRAF V600E mutation, than on ETV1 gene amplification. Consequently, therapeutic inhibition of BRAF and the downstream MAPK pathway also down-regulates oncogenic ETV1 expression.
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downregulation of cic does not associate with overexpression of ETV1 or map kinase pathway activation in gastrointestinal stromal tumors
Cancer Investigation, 2014Co-Authors: Sebastian F Schoppmann, Matthias Preusser, Aysegul Ilhanmutlu, Nadine Nirtl, Berthold Streubel, Gerda Ricken, Peter BirnerAbstract:ETV1 is a key factor in gastrointestinal stromal tumors (GIST), and is promoted by CIC downregulation in melanoma. We investigated CIC, ETV1, and the MAPK pathway in GIST. Downregulation of CIC protein levels as assessed by immunostaining was seen in 17/144 GIST, but was not associated with ETV1 or pMEK1/2 expression, KIT and PDGFRA mutations, copy number variations (CNV) of 19q13, and clinical factors. However, the data indicate that the incidence of CIC downregulation may differ for GISTs in different locations in the gastrointestinal tract, and that CNV of 19q13 is associated with shorter disease-free survival.
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downregulation of phosphatidylethanolamine binding protein 1 associates with clinical risk factors in gastrointestinal stromal tumors but not with activation of the raf 1 mek ETV1 pathway
Cancer Letters, 2013Co-Authors: Sebastian F Schoppmann, Andrea Beer, Nadine Nirtl, Berthold Streubel, Ahmed Bassalamah, Thomas Brodowicz, Peter BirnerAbstract:Abstract Aim of this study was to investigate phosphatidylethanolamine binding protein 1 (PEBP1) in GIST and its relations with MEK1/2 activation and ETV1 by immunohistochemistry. Loss of PEBP1 was found in 22/161 (13.7%) GIST, was associated with clinical risk factors and with a trend towards shorter disease free survival, but not with pMEK1/2 and ETV1 expression. So downregulation of PEBP1 does not activate the Ras-Raf-1-MEK1/2-ERK1/2 pathway by phosphorylation of MEK1/2 and does not influence ETV1 expression in GIST. Loss of PEBP1 associates with clinical risk factors, but since no significant influence on survival was found, further studies are required.
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mapkap kinase 2 overexpression influences prognosis in gastrointestinal stromal tumors and associates with copy number variations on chromosome 1 and expression of p38 map kinase and ETV1
Clinical Cancer Research, 2012Co-Authors: Peter Birner, Andrea Beer, Ursula Vinatzer, Susanne Stary, Romana Hoftberger, Nadine Nirtl, F Wrba, Berthold Streubel, Sebastian F SchoppmannAbstract:Purpose: ETV1 has been proposed to be activated by KIT mutations in gastrointestinal stromal tumors (GIST). The aim of the study was to evaluate the clinical role of ETV1 and associated proteins in GIST. Experimental Design: Expressions of ETV1, MAPKAP kinase 2 (MAPKAPK2), phosphorylated p38 MAP kinase (pp38), phosphorylated MSK1 (pMSK1), phosphorylated RSK1, COP1, and KIT protein were determined immunohistochemically in 139 GISTs. Sequence analysis of KIT , PDGFRA , and MAPKAPK2 and FISHs of ETV1 as well as chromosomes 1 and 7 were done. Results: Prominent ETV1 expression was seen in 50% of GISTs, but no correlation with clinical outcome was found. Correlation of ETV1 expression and KIT mutation was seen in 60% of cases. MAPKAPK2 overexpression ( n = 62/44.6%) correlated with pp38 expression ( P = 0.021, χ 2 test) and alterations of chromosome 1 ( n = 17, P = 0.024, χ 2 test). In one of 20 sequenced cases with high MAKAPK2 expression, a putative damaging MAPKAPK2 gene mutation was found. All relapsing GISTs with very low/low risk according to Fletcher showed high MAPKAPK2 and KIT expression. MAPKAPK2 overexpression was an independent prognostic factor for disease-free survival ( P = 0.006, Cox regression). Conclusion: ETV1 is not universally overexpressed in GIST and seems to also be induced by pathways other than KIT mutation. Nevertheless, its clinical relevance is low. Overexpression of ETV1 inhibitor MAPKAPK2 is associated with shorter survival in GIST, indicating a clinically relevant role of this gene not reported previously. Patients with low-risk GISTs showing MAPKAPK2 overexpression might profit from early adjuvant tyrosine kinase inhibitor therapy. Clin Cancer Res; 18(7); 1879–87. ©2012 AACR .
Aykut Uren - One of the best experts on this subject based on the ideXlab platform.
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Abstract 2949: YK-4-279 is a small molecule inhibitor of ETV1 and inhibits metastasis in a mouse model
Cancer Research, 2014Co-Authors: Said Rahim, Milton L Brown, Jeffrey A Toretsky, Sarah Justvig, Sung-hyeok Hong, Perrer N. Tosso, Haydar Çelik, Yasemin Sayedigar-kont, Colm Morrissey, Aykut UrenAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The erythroblastosis virus E26 transforming sequences (ETS) family of transcription factors consists of a highly conserved group of genes that play important roles in cellular proliferation, differentiation, migration and invasion. Chromosomal translocations fusing ETS factors to promoters of androgen responsive genes have been found in a majority of prostate cancers, including the most clinically aggressive forms. ERG and ETV1 are the most commonly translocated ETS proteins. Over-expression of these proteins in prostate cancer cells results in a more invasive phenotype. The high prevalence of these rearrangements, and their biological significance represents a novel therapeutic target for the treatment of prostate cancer. We recently demonstrated that the small molecule YK-4-279 inhibits ERG and ETV1 biological activity in fusion-positive prostate cancer cells leading to decreased motility and invasion in-vitro. Here, we present our findings in an in-vivo mouse xenograft model. SCID-beige mice were subcutaneously implanted with fusion-positive LNCaP and fusion-negative PC-3 tumors. Animals were treated with YK-4-279 and its effect on tumor size, lung metastasis and survival were observed. YK-4-279 treatment resulted in decreased tumor size in the LNCaP cohort only. A reduction in tumor metastasis to the lungs was observed in compound treated LNCaP animals with comparable tumor sizes. YK-4-279 also increased survival in LNCaP mice. Expression of ETV1 target genes MMP7, FKBP10 and GLYATL2 was reduced as well. ETS fusion-negative PC-3 xenografts were unresponsive to the compound. YK-4-279 is a chiral molecule that exists as a racemic mixture of R and S enantiomers. As part of this study, we also established that (S) -YK-4-279 is the active enantiomer in prostate cancer cells. (S) -YK-4-279 binds to ETV1 with comparable kinetics as the racemic mixture and inhibits ETV1 activity. (R) -YK-4-279 does not demonstrate ETV1 binding or inhibition. Our results demonstrate that YK-4-279 is a potent inhibitor of ETV1 and should be further evaluated for its clinical applications in prostate cancer. Citation Format: Said Rahim, Sarah Justvig, Sung-Hyeok Hong, Perrer Tosso, Haydar Celik, Yasemin Sayedigar-Kont, Milton Brown, Colm Morrissey, Jeffrey Toretsky, Aykut Uren. YK-4-279 is a small molecule inhibitor of ETV1 and inhibits metastasis in a mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2949. doi:10.1158/1538-7445.AM2014-2949
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yk 4 279 inhibits erg and ETV1 mediated prostate cancer cell invasion
PLOS ONE, 2011Co-Authors: Said Rahim, Elspeth M Beauchamp, Yali Kong, Milton L Brown, Jeffrey A Toretsky, Aykut UrenAbstract:Background Genomic rearrangements involving the ETS family of transcription factors occur in 40–70% of prostate cancer cases. ERG and ETV1 are the most common ETS members observed in these genetic alterations. The high prevalence of these rearrangements and their biological significance represents a novel therapeutic target for the treatment of prostate cancer. Methods and Findings We recently reported the development of YK-4-279, a small molecule inhibitor of EWS-FLI1 oncoprotein in Ewing's Sarcoma. Since ERG and ETV1 belong to the same class of ETS factors as FLI1, we tested the ability of YK-4-279 to inhibit biological functions of ERG and ETV1 proteins in prostate cancer. YK-4-279 inhibited ERG and ETV1 mediated transcriptional activity in a luciferase assay. YK-4-279 also decreased ERG and ETV1 downstream target mRNA and protein expression in ETV1-fusion positive LNCaP and ERG fusion positive VCaP cells. YK-4-279 reduced the motility of LNCaP cells in a scratch assay and the invasive phenotype of both LNCaP and VCaP cells in a HUVEC invasion assay. Fusion-negative PC3 cells were unresponsive to YK-4-279. SiRNA mediated ERG knockdown in VCaP cells resulted in a loss of drug responsiveness. Concurrently, transient ERG expression in PC-3 cells resulted in increased invasive potential, which was reduced by YK-4-279. Conclusion These data demonstrate that YK-4-279 inhibits ERG and ETV1 biological activity in fusion-positive prostate cancer cells leading to decreased motility and invasion. Therefore, YK-4-279 may have an impact on metastasis in prostate cancer and it may be further evaluated for its clinical applications in prostate cancer in addition to Ewing's sarcoma.
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abstract 663 yk 4 279 inhibits erg and ETV1 mediated prostate cancer cell invasion
Cancer Research, 2011Co-Authors: Said Rahim, Elspeth M Beauchamp, Yali Kong, Milton L Brown, Jeffrey A Toretsky, Aykut UrenAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Chromosomal translocations involving the ETS family of transcription factors are found in a majority of prostate cancers, including the most clinically aggressive forms. These translocations produce a chimeric gene, which fuses the promoter region of an androgen responsive gene, such as TMPRSS2, to the coding region of ETS factors, most frequently ETV1 or ERG. Over-expression of ETS factors in prostate cancer cells results in a more invasive phenotype. The high prevalence of these rearrangements, and their biological significance represents a novel therapeutic target for the treatment of prostate cancer. We recently reported the development of YK-4-279, a small molecule inhibitor of EWS-FLI1 oncoprotein in Ewing's Sarcoma. ERG and ETV1 belong to the same class of ETS factors as FLI1. Due to the close homology of FLI1 with ERG and ETV1, we tested the ability of YK-4-279 to inhibit ETS biological activity in prostate cell-lines such as VCaP and LNCaP that demonstrate androgen dependent ERG and ETV1 expression, respectively. YK-4-279 inhibited ERG and ETV1 mediated transcription of target genes such as PLAU, PLAT, ADAM19 and MMP-13, which are involved in breakdown of the extracellular matrix and metastasis. YK-4-279 reduced the motility and invasive phenotype of ETV1-fusion positive LNCaP cells and ERG fusion-positive VCaP cells in in vitro invasion assays. However, ETS fusion-negative PC-3 cells were unresponsive to YK-4-279. ERG knockdown in VCaP cells resulted in a loss of drug responsiveness. Transient ERG expression in PC-3 cells resulted in an increased invasive phenotype, which was reduced by YK-4-279. Our results demonstrate that YK-4-279 inhibits ERG and ETV1 biological activity in fusion-positive prostate cancer cells leading to decreased motility and invasion. Therefore, YK-4-279 may have an impact on metastasis in prostate cancer, which is a leading cause of death, and it may be further evaluated for its clinical applications in prostate cancer, in addition to Ewing's sarcoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 663. doi:10.1158/1538-7445.AM2011-663
Wenjian Wang - One of the best experts on this subject based on the ideXlab platform.
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mir 17 5p suppresses cell proliferation and invasion by targeting ETV1 in triple negative breast cancer
BMC Cancer, 2017Co-Authors: Jie Li, Jiong Bi, Longjuan Zhang, Lianzhou Chen, Weiming Lv, Guangqi Chang, Shenming Wang, Mao Ouyang, Wenjian WangAbstract:Abstract Background Triple-negative breast cancer (TNBC) is the malignancy with the worst outcome among all breast cancer subtypes. We reported that ETV1 is a significant oncogene in TNBC tumourigenesis. Consequently, investigating the critical regulatory microRNAs (miRNAs) of ETV1 may be beneficial for TNBC targeted therapy. Methods We performed in situ hybridization (ISH) and immunohistochemistry (IHC) to detect the location of miR-17-5p and ETV1 in TNBC patient samples, respectively. miR-17-5p expression in TNBC tissues and cell lines was assessed by quantitative real-time PCR (qRT-PCR). ETV1 expression was evaluated by qRT-PCR, western blotting and IHC. Cell Counting Kit-8 (CCK-8), colony formation, Transwell and wound closure assays were utilized to determine the TNBC cell proliferation and migration capabilities. In vivo tumour metastatic assays were performed in a zebra fish model. Results The abundance of miR-17-5p was significantly decreased in TNBC cell lines and clinical TNBC tissues. The miR-17-5p expression levels were closely correlated with tumour size ( P P r = −0.28, P = 3.88 × 10 −3 ). Luciferase reporter assay confirmed that ETV1 was a direct target of miR-17-5p. Forced expression of miR-17-5p in MDA-MB-231 or BT549 cells significantly decreased ETV1 expression and suppressed cell proliferation, migration in vitro and tumour metastasis in vivo. However, rescuing the expression of ETV1 in the presence of miR-17-5p significantly recovered the cell phenotype. High miR-17-5p expression was associated with a significantly favourable prognosis, in either the ETV1-positive or ETV1-negative groups (log-rank test, P P Conclusions Our data indicate that miR-17-5p acts as a tumour suppressor in TNBC by targeting ETV1, and a low-abundance of miR-17-5p may be involved in the pathogenesis of TNBC. These findings indicate that miR-17-5p may be a therapeutic target for TNBC.
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cop1 the negative regulator of ETV1 influences prognosis in triple negative breast cancer
BMC Cancer, 2015Co-Authors: Mao Ouyang, Jie Li, Jiong Bi, Guangqi Chang, Shenming Wang, Hua Wang, Weiming Lu, Wenjian WangAbstract:Background ETS variant 1 (ETV1) and E3 ubiquitin ligase constitutive photomorphogenetic 1 (COP1) have been proposed to be a pair of oncogene and tumor suppressor. However, the co-existing status of ETV1 and COP1 in triple-negative breast cancer (TNBC) and their predictive role in determining the patient’s outcome are uncertain.
Sebastian F Schoppmann - One of the best experts on this subject based on the ideXlab platform.
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mk2 and ETV1 are prognostic factors in esophageal adenocarcinomas
Journal of Cancer, 2018Co-Authors: Gerd Jomrich, Florian Maroske, Jasmin Stieger, Matthias Preusser, Aysegul Ilhanmutlu, Daniel Winkler, Ivan Kristo, Matthias Paireder, Sebastian F SchoppmannAbstract:Background. Esophageal cancer is ranked in the top ten of diagnosed tumors worldwide. Even though improvements in survival could be noticed over the last years, prognosis remains poor. ETS translocation variant 1 (ETV1) is a member of a family of transcription factors and is phosphorylated by mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2). Aim of this study was to evaluate the prognostic role of MK2 and ETV1 in esophageal cancer. Methods. Consecutive patients that underwent surgical resection at the department of surgery at the Medical University of Vienna between 1991 and 2012 were included into this study. After microscopic analysis, tissue micro arrays (TMAs) were created and immunohistochemistry was performed with antibodies against MK2 and ETV1. Results. 323 patients were included in this study. Clinical data was achieved from a prospective patient data base. Nuclear overexpression of MK2 was observed in 143 (44.3%) cases for nuclear staining and in 142 (44.0%) cases a cytoplasmic overexpression of MK2 was observed. Nuclear and cytoplasmic ETV1 overexpression was detected in 20 cases (6.2%) and 30 cases (9.3%), respectively. In univariate survival analysis, cMK2 and nETV1 were found to be significantly associated with patients' overall survival. Whereas overexpression of cMK2 was associated with shorter, nETV1 was associated with longer overall survival. In multivariate survival analysis, both cMK2 and nETV1 were found to be independent prognostic factors for the subgroup of EAC as well. Discussion. Expression of MK2 and ETV1 are prognostic factors in patients, with esophageal adenocarcinoma.
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MAP kinase activity supported by BRAF ^ V600E mutation rather than gene amplification is associated with ETV1 expression in melanoma brain metastases
Archives of Dermatological Research, 2014Co-Authors: Peter Birner, Sebastian F Schoppmann, Anna S. Berghoff, Carina Dinhof, Christine Pirker, David Capper, Peter Petzelbauer, Andreas Deimling, Walter Berger, Matthias PreusserAbstract:In primary melanoma, ETV1 transcription factor was suggested to be activated mainly by gene amplification and to promote tumor growth in cooperation with BRAF ^ V600E . Aim of this study was to investigate ETV1 expression in human melanoma with a focus on brain metastases. We investigated ETV1 in 68 human melanoma brain metastases using FISH for ETV1 gene (located at chromosome 7p21) and centromere chromosome 7 and immunohistochemistry for ETV1, BRAF ^ V600E , and ETV1/BRAF associated proteins pMSK1, pRSK1, pp38, pMEK1/2, MAPKAP kinase 2, CIC, HIF-1alpha and Ki-67. We further studied ETV1 copy number variations in 32 melanoma cell lines from primary and metastatic lesions using array CGH. The influence of the MAP kinase pathway activity on ETV1 mRNA and protein expression under BRAF wild-type and BRAF ^ V600E conditions were determined in melanoma cell lines using qRT-PCR and Western Blot. No ETV1 high grade amplifications were observed in tissue samples, but low grade ETV1 gene amplifications were found in 7 (10.3 %) melanoma brain metastases. ETV1 protein expression in tissue samples (15 %) correlated with BRAF ^ V600E status ( p = 0.007) and HIF-1alpha expression ( p = 0.049), but not with ETV1 gene dose. Application of the BRAF^V600E-specific inhibitor vemurafenib and the BRAF^V6ooE/V600K-inhibitor dabrafenib revealed predominant regulation of ETV-1 mRNA and protein via MAPK-pathway. ETV1 expression is a rare event in human melanoma and seems to be rather based on hyperactivation of MAPK signals, by BRAF ^ V600E mutation, than on ETV1 gene amplification. Consequently, therapeutic inhibition of BRAF and the downstream MAPK pathway also down-regulates oncogenic ETV1 expression.
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map kinase activity supported by braf v600e mutation rather than gene amplification is associated with ETV1 expression in melanoma brain metastases
Archives of Dermatological Research, 2014Co-Authors: Peter Birner, Sebastian F Schoppmann, Anna S. Berghoff, Carina Dinhof, Christine Pirker, David Capper, Peter Petzelbauer, Andreas Deimling, Walter Berger, Matthias PreusserAbstract:In primary melanoma, ETV1 transcription factor was suggested to be activated mainly by gene amplification and to promote tumor growth in cooperation with BRAF V600E . Aim of this study was to investigate ETV1 expression in human melanoma with a focus on brain metastases. We investigated ETV1 in 68 human melanoma brain metastases using FISH for ETV1 gene (located at chromosome 7p21) and centromere chromosome 7 and immunohistochemistry for ETV1, BRAF V600E , and ETV1/BRAF associated proteins pMSK1, pRSK1, pp38, pMEK1/2, MAPKAP kinase 2, CIC, HIF-1alpha and Ki-67. We further studied ETV1 copy number variations in 32 melanoma cell lines from primary and metastatic lesions using array CGH. The influence of the MAP kinase pathway activity on ETV1 mRNA and protein expression under BRAF wild-type and BRAF V600E conditions were determined in melanoma cell lines using qRT-PCR and Western Blot. No ETV1 high grade amplifications were observed in tissue samples, but low grade ETV1 gene amplifications were found in 7 (10.3 %) melanoma brain metastases. ETV1 protein expression in tissue samples (15 %) correlated with BRAF V600E status (p = 0.007) and HIF-1alpha expression (p = 0.049), but not with ETV1 gene dose. Application of the BRAFV600E-specific inhibitor vemurafenib and the BRAFV6ooE/V600K-inhibitor dabrafenib revealed predominant regulation of ETV-1 mRNA and protein via MAPK-pathway. ETV1 expression is a rare event in human melanoma and seems to be rather based on hyperactivation of MAPK signals, by BRAF V600E mutation, than on ETV1 gene amplification. Consequently, therapeutic inhibition of BRAF and the downstream MAPK pathway also down-regulates oncogenic ETV1 expression.
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downregulation of cic does not associate with overexpression of ETV1 or map kinase pathway activation in gastrointestinal stromal tumors
Cancer Investigation, 2014Co-Authors: Sebastian F Schoppmann, Matthias Preusser, Aysegul Ilhanmutlu, Nadine Nirtl, Berthold Streubel, Gerda Ricken, Peter BirnerAbstract:ETV1 is a key factor in gastrointestinal stromal tumors (GIST), and is promoted by CIC downregulation in melanoma. We investigated CIC, ETV1, and the MAPK pathway in GIST. Downregulation of CIC protein levels as assessed by immunostaining was seen in 17/144 GIST, but was not associated with ETV1 or pMEK1/2 expression, KIT and PDGFRA mutations, copy number variations (CNV) of 19q13, and clinical factors. However, the data indicate that the incidence of CIC downregulation may differ for GISTs in different locations in the gastrointestinal tract, and that CNV of 19q13 is associated with shorter disease-free survival.
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downregulation of phosphatidylethanolamine binding protein 1 associates with clinical risk factors in gastrointestinal stromal tumors but not with activation of the raf 1 mek ETV1 pathway
Cancer Letters, 2013Co-Authors: Sebastian F Schoppmann, Andrea Beer, Nadine Nirtl, Berthold Streubel, Ahmed Bassalamah, Thomas Brodowicz, Peter BirnerAbstract:Abstract Aim of this study was to investigate phosphatidylethanolamine binding protein 1 (PEBP1) in GIST and its relations with MEK1/2 activation and ETV1 by immunohistochemistry. Loss of PEBP1 was found in 22/161 (13.7%) GIST, was associated with clinical risk factors and with a trend towards shorter disease free survival, but not with pMEK1/2 and ETV1 expression. So downregulation of PEBP1 does not activate the Ras-Raf-1-MEK1/2-ERK1/2 pathway by phosphorylation of MEK1/2 and does not influence ETV1 expression in GIST. Loss of PEBP1 associates with clinical risk factors, but since no significant influence on survival was found, further studies are required.
Ralf Janknecht - One of the best experts on this subject based on the ideXlab platform.
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relationship between ets transcription factor ETV1 and tgf β regulated smad proteins in prostate cancer
Scientific Reports, 2019Co-Authors: Sangphil Oh, Sook Shin, Hoogeun Song, Joseph P Grande, Ralf JanknechtAbstract:The ETS transcription factor ETV1 is frequently overexpressed in aggressive prostate cancer, which is one underlying cause of this disease. Accordingly, transgenic mice that prostate-specifically overexpress ETV1 develop prostatic intraepithelial neoplasia. However, progression to the adenocarcinoma stage is stifled in these mice, suggesting that inhibitory pathways possibly preclude ETV1 from exerting its full oncogenic potential. Here we provide evidence that TGF-β/SMAD signaling represents such an inhibitory pathway. First, we discovered that ETV1 forms complexes with SMAD4. Second, SMAD2, SMAD3 and SMAD4 overexpression impaired ETV1’s ability to stimulate gene transcription. Third, TGF-β1 inhibited ETV1-induced invasion by benign RWPE-1 prostate cells. Fourth, increased expression of SMAD3 and SMAD4 was observable in prostates of ETV1 transgenic mice. Conversely, we found that ETV1 may enhance TGF-β signaling in PC3 prostate cancer cells, revealing a different facet of the ETV1/TGF-β interplay. Altogether, these data provide more insights into the regulation and action of ETV1 and additionally suggest that TGF-β/SMAD signaling exerts its tumor suppressive activity, at least in part, by curtailing the oncogenic potential of ETV1 in prostatic lesions.
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14 3 3 proteins modulate the ets transcription factor ETV1 in prostate cancer
Cancer Research, 2013Co-Authors: Sangphil Oh, Sook Shin, Stan Lightfoot, Ralf JanknechtAbstract:Overexpression of the ETS-related transcription factor ETV1 can initiate neoplastic transformation of the prostate. ETV1 activity is highly regulated by phosphorylation, but the underlying mechanisms are unknown. Here we report that all 14-3-3 proteins, with the exception of the tumor suppressor 14-3-3σ, can bind to ETV1 in a condition manner dictated by its prominent phosphorylation site S216. All non-σ 14-3-3 proteins synergized with ETV1 to activate transcription of its target genes MMP-1 and MMP-7, which regulate extracellular matrix in the prostate tumor microenvironment. S216 mutation or 14-3-3τ downregulation was sufficient to reduce ETV1 protein levels in prostate cancer cells, indicating that non-σ 14-3-3 proteins protect ETV1 from degradation. Notably, S216 mutation also decreased ETV1-dependent migration and invasion in benign prostate cells. Downregulation of 14-3-3τ reduced prostate cancer cell invasion and growth in the same manner as ETV1 attenuation. Lastly, we showed that 14-3-3τ and 14-3-3e were overexpressed in human prostate tumors. Taken together, our results demonstrated that non-σ 14-3-3 proteins are important modulators of ETV1 function that promote prostate tumorigenesis.
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ETS variant 1 regulates matrix metalloproteinase-7 transcription in LNCaP prostate cancer cells
Oncology Reports, 2012Co-Authors: Sook Shin, Sangphil Oh, Seayoon An, Ralf JanknechtAbstract:: Prostate cancer is characterized by the recurrent translocation of ETS transcription factors, including ETS variant 1 (ETV1) [also known as ETS-related 81 (ER81)]. Transgenic ETV1 mice develop prostatic intraepithelial neoplasia, yet the mechanisms by which ETV1 exerts its deleterious function remain largely unexplored. In this study, we demonstrated that ETV1 is capable of binding to the matrix metalloproteinase-7 (MMP-7) gene promoter both in vitro and in vivo. ETV1 stimulated the activity of the MMP-7 promoter, which was suppressed upon mutation of two ETV1 binding sites located within 200 base pairs upstream of the MMP-7 transcription start site. ETV1 overexpression in human LNCaP prostate cancer cells induced endogenous MMP-7 gene transcription, whereas ETV1 downregulation had the opposite effect. While MMP-7 overexpression did not influence LNCaP cell proliferation, it increased cell migration, which may be important during later stages of tumorigenesis. Finally, MMP-7 mRNA was significantly overexpressed in human prostate tumors compared to normal tissue. Together, these results showed that MMP-7 is a bona fide ETV1 target gene, implicating that MMP-7 upregulation is partially responsible for the oncogenic effects of ETV1 in the prostate.
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ETV1 4 and 5 an oncogenic subfamily of ets transcription factors
Biochimica et Biophysica Acta, 2012Co-Authors: Sangphil Oh, Sook Shin, Ralf JanknechtAbstract:The homologous ETV1, ETV4 and ETV5 proteins form the PEA3 subfamily of ETS transcription factors. In Ewing tumors, chromosomal translocations affecting ETV1 or ETV4 are an underlying cause of carcinogenesis. Likewise, chromosomal rearrangements of the ETV1, ETV4 or ETV5 gene occur in prostate tumors and are thought to be one of the major driving forces in the genesis of prostate cancer. In addition, these three ETS proteins are implicated in melanomas, breast and other types of cancer. Complex posttranslational modifications govern the activity of PEA3 factors, which can promote cell proliferation, motility and invasion. Here, we review evidence for a role of ETV1, 4 and 5 as oncoproteins and describe modes of their action. Modulation of their activation or interaction with cofactors as well as inhibiting crucial target gene products may ultimately be exploited to treat various cancers that are dependent on the PEA3 group of ETS transcription factors.
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induction of prostatic intraepithelial neoplasia and modulation of androgen receptor by ets variant 1 ets related protein 81
Cancer Research, 2009Co-Authors: Sook Shin, Scott M. Dehm, Joseph P Grande, Jin Fang, Jan M Van Deursen, Donald J Tindall, Jan Marie Munz, George Vasmatzis, Ralf JanknechtAbstract:ETS variant 1 (ETV1), also known as ETS-related protein 81, is overexpressed in prostate tumors, but whether and how this transcription factor affects tumorigenesis has remained elusive. Here, we show that ETV1 is primarily overexpressed in the most aggressive human prostate tumors. Transgenic ETV1 mice developed prostatic intraepithelial neoplasia as well as hyperplasia/neoplasia in seminal vesicles. Moreover, ETV1 cooperated with the androgen receptor (AR) to bind to the prostate-specific antigen enhancer and stimulate gene transcription. Consistent with its ability to physically interact with AR, ETV1 rendered an ETV1 binding site–driven reporter androgen inducible, and, on the other hand, ETV1 superinduced transcription from an AR binding site on androgen stimulation. In conclusion, our study substantiates that ETV1 overexpression is an underlying cause in the development of prostate and possibly also seminal vesicle cancer. Its interaction with and activation of AR provides a molecular mechanism on how ETV1 exerts its deleterious function. Thus, inhibiting ETV1 or blocking its interaction with AR may represent novel strategies in prostate cancer therapy. [Cancer Res 2009;69(20):8102–10]