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ETV4 (ets variant 4)

Written2010-11Yasuyoshi Miyata
Department of Urology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan

(Note : for Links provided by Atlas : click)


Other aliasE1A-F
LocusID (NCBI) 2118
Atlas_Id 133
Location 17q21.31  [Link to chromosome band 17q21]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CANT1 (17q25.3) / ETV4 (17q21.31)DDX5 (17q23.3) / ETV4 (17q21.31)DHX8 (17q21.31) / ETV4 (17q21.31)
ETV4 (17q21.31) / CANT1 (17q25.3)ETV4 (17q21.31) / CCL16 (17q12)ETV4 (17q21.31) / DDX5 (17q23.3)
ETV4 (17q21.31) / EDIL3 (5q14.3)ETV4 (17q21.31) / EWSR1 (22q12.2)ETV4 (17q21.31) / KLK2 (19q13.33)
ETV4 (17q21.31) / TMPRSS2 (21q22.3)EWSR1 (22q12.2) / ETV4 (17q21.31)KLK2 (19q13.33) / ETV4 (17q21.31)
SLC45A3 (1q32.1) / ETV4 (17q21.31)TMPRSS2 (21q22.3) / ETV4 (17q21.31)UBTF (17q21.31) / ETV4 (17q21.31)
XPO7 (8p21.3) / ETV4 (17q21.31)


  GeneLoc map region.
Description The gene spans approximately 30 kb and contained 14 exons. The largest exon (901 bp) contains the end of the ETS domain, the carboxy-terminal domain and the 3'-untranslated region. The remaining exons varied from 48 bp (exon 5) to 266 bp (exon 9).


Description ETV4 is a member of ets-oncogene family transcription factors that were cloned by the ability to bind to enhancer motifs of the adenovirus E1A gene (Lavia et al., 2003). It is composed of 555 amino acids, which has a molecular weight ranging 61~70 kDa.
Localisation Nuclear (Monté et al., 1994; Takahashi et al., 2005). Ubiquitinated protein is localized in the dot-like structure in the nuclear (Takahashi et al., 2005).
Function ETV4 is capable of regulating transcription by binding to the Ets-binding site in the promoter of its target genes. Biologically, it contributes in a number of processes including neuronal pathfinding, mammary gland development, and male sexual function (Laing et al., 2000; Ladle et al., 2002; Kurpios et al., 2003). In various malignancies, its over-expression has been observed and it was also associated with tumor progression and outcome of patients with these malignancies. As mechanism of such function, regulation of hepatocyte growth factor (HGF)-induced cell migration (Hakuma et al., 2005), HER2-mediated malignant potential (Benz et al., 1997), and other ETV4-related factors including cyclooxygenase (COX)-2 and matrix metalloproteinases (MMPs) have been reported (Higashino et al., 1995; Horiuchi et al., 2003; Shindoh et al., 2004). In addition, ETV4 promotes cell cycle progression via upregulation of cyclin D3 transcription in breast cancer cell (MDA231 cell) (Jiang et al., 2007). In contrast, ETV4 function as negative regulator of sonic hedgehog expression (Mao et al., 2009).

Implicated in

Entity Breast cancer
Disease Over-expression of ETV4 has been detected in human cancer cell lines (Baert et al., 1997). In animal model and human tissues, its over-expression was also found and it was associated with malignant potential including invasion and metastasis (Trimble et al., 1993; De Launoit et al., 2000; Benz et al., 1997; Bièche et al., 2004). Such ETV4-related functions are controlled via regulation of cyclin D3 transcription (Jiang et al., 2007), HER-2/Neu (Benz et al., 1997), and MMPs (Bièche et al., 2004).
Entity Gastric cancer
Disease Correlated with tumor progression via up-regulation of matrilysin in human tissues (Yamamoto et al., 2004).
Entity Lung cancer
Disease ETV4 expression was not detected in normal lung tissues. On the other hand, it is expressed in distal lung epithelium during lung development and in human lung cancer cells (Hiroumi et al., 2001; Liu et al., 2003). It was reported to be associated with cell invasion (Hiroumi et al., 2001) and metastasis via regulation of caveolin-1 transcription (Sloan et al., 2009) and Met-related factors (Hakuma et al., 2005).
Entity Malignant melanoma
Disease In cell lines, ETV4 plays important roles for malignant behavior including invasion and metastasis thorough up-regulation of MT1-MMP (Hata et al., 2008).
Entity Prostate cancer
Disease In human tissues, its expression in cancer cell was significantly higher than that in normal cells and it was also positively associated with pT stage. This finding was influenced with regulation of MMP-7 and MMP-9, but not of MMP-1, MMP-3, and MMP-14 (MT1-MMP) (Maruta et al., 2009).
Entity Colorectal cancer
Disease In early stage of colorectal carcinogenesis, its over-expression plays important roles through MMPs, COX-2, and iNos (Nosho et al., 2005).




Expression of the PEA3 group of ETS-related transcription factors in human breast-cancer cells.
Baert JL, Monte D, Musgrove EA, Albagli O, Sutherland RL, de Launoit Y.
Int J Cancer. 1997 Mar 4;70(5):590-7.
PMID 9052761
HER2/Neu and the Ets transcription activator PEA3 are coordinately upregulated in human breast cancer.
Benz CC, O'Hagan RC, Richter B, Scott GK, Chang CH, Xiong X, Chew K, Ljung BM, Edgerton S, Thor A, Hassell JA.
Oncogene. 1997 Sep 25;15(13):1513-25.
PMID 9380403
Expression of PEA3/E1AF/ETV4, an Ets-related transcription factor, in breast tumors: positive links to MMP2, NRG1 and CGB expression.
Bieche I, Tozlu S, Girault I, Onody P, Driouch K, Vidaud M, Lidereau R.
Carcinogenesis. 2004 Mar;25(3):405-11. Epub 2003 Nov 21.
PMID 14633660
E1AF/PEA3 activates the Rho/Rho-associated kinase pathway to increase the malignancy potential of non-small-cell lung cancer cells.
Hakuma N, Kinoshita I, Shimizu Y, Yamazaki K, Yoshida K, Nishimura M, Dosaka-Akita H.
Cancer Res. 2005 Dec 1;65(23):10776-82.
PMID 16322223
Expression of E1AF, an ets-oncogene transcription factor, highly correlates with malignant phenotype of malignant melanoma through up-regulation of the membrane-type-1 matrix metalloproteinase gene.
Hata H, Kitamura T, Higashino F, Hida K, Yoshida K, Ohiro Y, Totsuka Y, Kitagawa Y, Shindoh M.
Oncol Rep. 2008 May;19(5):1093-8.
PMID 18425363
Ets-related protein E1A-F can activate three different matrix metalloproteinase gene promoters.
Higashino F, Yoshida K, Noumi T, Seiki M, Fujinaga K.
Oncogene. 1995 Apr 6;10(7):1461-3.
PMID 7731700
Expression of E1AF/PEA3, an Ets-related transcription factor in human non-small-cell lung cancers: its relevance in cell motility and invasion.
Hiroumi H, Dosaka-Akita H, Yoshida K, Shindoh M, Ohbuchi T, Fujinaga K, Nishimura M.
Int J Cancer. 2001 Sep;93(6):786-91.
PMID 11519038
Association of ets-related transcriptional factor E1AF expression with tumour progression and overexpression of MMP-1 and matrilysin in human colorectal cancer.
Horiuchi S, Yamamoto H, Min Y, Adachi Y, Itoh F, Imai K.
J Pathol. 2003 Aug;200(5):568-76.
PMID 12898592
E1AF promotes breast cancer cell cycle progression via upregulation of Cyclin D3 transcription.
Jiang J, Wei Y, Liu D, Zhou J, Shen J, Chen X, Zhang S, Kong X, Gu J.
Biochem Biophys Res Commun. 2007 Jun 22;358(1):53-8. Epub 2007 Apr 18.
PMID 17467662
Function of PEA3 Ets transcription factors in mammary gland development and oncogenesis.
Kurpios NA, Sabolic NA, Shepherd TG, Fidalgo GM, Hassell JA.
J Mammary Gland Biol Neoplasia. 2003 Apr;8(2):177-90. (REVIEW)
PMID 14635793
The role of the ETS gene PEA3 in the development of motor and sensory neurons.
Ladle DR, Frank E.
Physiol Behav. 2002 Dec;77(4-5):571-6.
PMID 12527001
Male sexual dysfunction in mice bearing targeted mutant alleles of the PEA3 ets gene.
Laing MA, Coonrod S, Hinton BT, Downie JW, Tozer R, Rudnicki MA, Hassell JA.
Mol Cell Biol. 2000 Dec;20(24):9337-45.
PMID 11094084
Emerging roles of DNA tumor viruses in cell proliferation: new insights into genomic instability.
Lavia P, Mileo AM, Giordano A, Paggi MG.
Oncogene. 2003 Sep 29;22(42):6508-16. (REVIEW)
PMID 14528275
Role for ETS domain transcription factors Pea3/Erm in mouse lung development.
Liu Y, Jiang H, Crawford HC, Hogan BL.
Dev Biol. 2003 Sep 1;261(1):10-24.
PMID 12941618
Fgf-dependent Etv4/5 activity is required for posterior restriction of Sonic Hedgehog and promoting outgrowth of the vertebrate limb.
Mao J, McGlinn E, Huang P, Tabin CJ, McMahon AP.
Dev Cell. 2009 Apr;16(4):600-6.
PMID 19386268
E1AF expression is associated with extra-prostatic growth and matrix metalloproteinase-7 expression in prostate cancer.
Maruta S, Sakai H, Kanda S, Hayashi T, Kanetake H, Miyata Y.
APMIS. 2009 Nov;117(11):791-6.
PMID 19845529
Molecular cloning and characterization of human ERM, a new member of the Ets family closely related to mouse PEA3 and ER81 transcription factors.
Monte D, Baert JL, Defossez PA, de Launoit Y, Stehelin D.
Oncogene. 1994 May;9(5):1397-406.
PMID 8152800
Association of Ets-related transcriptional factor E1AF expression with overexpression of matrix metalloproteinases, COX-2 and iNOS in the early stage of colorectal carcinogenesis.
Nosho K, Yoshida M, Yamamoto H, Taniguchi H, Adachi Y, Mikami M, Hinoda Y, Imai K.
Carcinogenesis. 2005 May;26(5):892-9. Epub 2005 Feb 3.
PMID 15695237
E1AF, an ets-oncogene family transcription factor.
Shindoh M, Higashino F, Kohgo T.
Cancer Lett. 2004 Dec 8;216(1):1-8. (REVIEW)
PMID 15500943
Increased PEA3/E1AF and decreased Net/Elk-3, both ETS proteins, characterize human NSCLC progression and regulate caveolin-1 transcription in Calu-1 and NCI-H23 NSCLC cell lines.
Sloan KA, Marquez HA, Li J, Cao Y, Hinds A, O'Hara CJ, Kathuria S, Ramirez MI, Williams MC, Kathuria H.
Carcinogenesis. 2009 Aug;30(8):1433-42. Epub 2009 May 29.
PMID 19483189
E1AF degradation by a ubiquitin-proteasome pathway.
Takahashi A, Higashino F, Aoyagi M, Yoshida K, Itoh M, Kobayashi M, Totsuka Y, Kohgo T, Shindoh M.
Biochem Biophys Res Commun. 2005 Feb 11;327(2):575-80.
PMID 15629152
PEA3 is overexpressed in mouse metastatic mammary adenocarcinomas.
Trimble MS, Xin JH, Guy CT, Muller WJ, Hassell JA.
Oncogene. 1993 Nov;8(11):3037-42.
PMID 7692372
Expression of ets-related transcriptional factor E1AF is associated with tumor progression and over-expression of matrilysin in human gastric cancer.
Yamamoto H, Horiuchi S, Adachi Y, Taniguchi H, Nosho K, Min Y, Imai K.
Carcinogenesis. 2004 Mar;25(3):325-32. Epub 2003 Nov 6.
PMID 14604892
The PEA3 group of ETS-related transcription factors. Role in breast cancer metastasis.
de Launoit Y, Chotteau-Lelievre A, Beaudoin C, Coutte L, Netzer S, Brenner C, Huvent I, Baert JL.
Adv Exp Med Biol. 2000;480:107-16. (REVIEW)
PMID 10959416


This paper should be referenced as such :
Miyata, Y
ETV4 (ets variant 4)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(7):554-556.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 5 ]
  t(17;17)(q21;q21) DHX08/ETV4
DHX8/ETV4 (17q21)
t(16;21)(p11;q22) FUS/ERG
t(17;17)(q21;q21) DHX08/ETV4
DHX8/ETV4 (17q21)

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 13 ]
  Soft Tissues: Angiomatoid fibrous histiocytoma
Bone tumors: an overview
Bone: Soft tissue chondroma with t(3;12)(q27;q15) HMGA2/LPP
Prostate tumors: an overview
Soft tissue tumors: an overview
Soft Tissues: Ewing's tumors/Primitive neurectodermal tumor with t(16;21)(p11;q22) FUS/ERG
t(1;17)(q32;q21) SLC45A3/ETV4
t(5;17)(p15;q21) ETV4/AHRR
t(8;17)(p21;q21) XPO7/ETV4
t(8;17)(q13;q21) NCOA2/ETV4
t(17;17)(q12;q21) ETV4/CCL16
UBTF/ETV4 (17q21)
t(17;17)(q21;q25) CANT1/ETV4

External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)2118
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
canSAR (ICR) (select the gene name)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Oct 18 17:35:42 CEST 2018

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