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ERG expression in prostate cancer: biological relevance and clinical implication

  • Review – Clinical Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Introduction

Screening for increased levels of prostate-specific antigen (PSA) has allowed early detection of a large majority of prostate cancer (PCa) cases. However, the relative lack of specificity of PSA has resulted in significant over-diagnosis and unnecessary treatment for indolent tumors. The fusion of the transmembrane protease serine 2 with E26 transformation-specific family genes, particularly ERG, is the most widespread genetic alteration in prostate cancer, and data suggest that it is more specific for neoplastic prostate disease and may be of added prognostic value and point toward molecular subtype of PCa.

Methods

In this review, retrospective studies and clinical trials were analyzed to highlight the recent advances in our understanding of the cellular consequence of ERG rearrangement, describe its interactions with other genetic and molecular pathways, and discuss its potential diagnostic and prognostic value.

Conclusion

ERG over-expression has an emerging role in the diagnosis of PCa pathology, although there is still debate about its prognostic value. Elucidation of the mechanisms of ERG gene rearrangements and expression promises novel therapeutic and diagnostic avenues for prostate cancer.

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References

  • Al Bashir S, Alshalalfa M, Hegazy SA, Dolph M, Donnelly B, Bismar TA (2014) Cysteine-rich secretory protein 3 (CRISP3), ERG and PTEN define a molecular subtype of prostate cancer with implication to patients’ prognosis. J Hematol Oncol 7:21. doi:10.1186/1756-8722-7-21

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ateeq B, Tomlins SA, Laxman B, Asangani IA, Cao Q, Cao X et al (2011) Therapeutic targeting of SPINK1-positive prostate cancer. Sci Transl Med 3(72):72ra17. doi:10.1126/scitranslmed.3001498

    Article  PubMed  PubMed Central  Google Scholar 

  • Attard G, Clark J, Ambroisine L, Fisher G, Kovacs G, Flohr P et al (2008) Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene 27(3):253–263. doi:10.1038/sj.onc.1210640

    Article  CAS  PubMed  Google Scholar 

  • Attiga FA, Fernandez PM, Weeraratna AT, Manyak MJ, Patierno SR (2000) Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteinases. Cancer Res 60(16):4629–4637

    CAS  PubMed  Google Scholar 

  • Badawi AF (2000) The role of prostaglandin synthesis in prostate cancer. BJU Int 85(4):451–462

    Article  CAS  PubMed  Google Scholar 

  • Baena E, Shao Z, Linn DE, Glass K, Hamblen MJ, Fujiwara Y et al (2013) ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients. Genes Dev 27(6):683–698. doi:10.1101/gad.211011.112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barfeld SJ, East P, Zuber V, Mills IG (2014) Meta-analysis of prostate cancer gene expression data identifies a novel discriminatory signature enriched for glycosylating enzymes. BMC Med Genomics 7(1):513. doi:10.1186/s12920-014-0074-9

    Article  PubMed  PubMed Central  Google Scholar 

  • Berg KD, Vainer B, Thomsen FB, Roder MA, Gerds TA, Toft BG et al (2014) ERG protein expression in diagnostic specimens is associated with increased risk of progression during active surveillance for prostate cancer. Eur Urol 66(5):851–860. doi:10.1016/j.eururo.2014.02.058

    Article  CAS  PubMed  Google Scholar 

  • Bettendorf O, Schmidt H, Staebler A, Grobholz R, Heinecke A, Boecker W et al (2008) Chromosomal imbalances, loss of heterozygosity, and immunohistochemical expression of TP53, RB1, and PTEN in intraductal cancer, intraepithelial neoplasia, and invasive adenocarcinoma of the prostate. Genes Chromosomes Cancer 47(7):565–572

    Article  CAS  PubMed  Google Scholar 

  • Bismar TA, Yoshimoto M, Vollmer RT, Duan Q, Firszt M, Corcos J et al (2011) PTEN genomic deletion is an early event associated with ERG gene rearrangements in prostate cancer. BJU Int 107(3):477–485. doi:10.1111/j.1464-410X.2010.09470.x

    Article  PubMed  Google Scholar 

  • Bismar TA, Yoshimoto M, Duan Q, Liu S, Sircar K, Squire JA (2012a) Interactions and relationships of PTEN, ERG, SPINK1 and AR in castration-resistant prostate cancer. Histopathology 60(4):645–652. doi:10.1111/j.1365-2559.2011.04116.x

    Article  PubMed  Google Scholar 

  • Bismar TA, Dolph M, Teng LH, Liu S, Donnelly B (2012b) ERG protein expression reflects hormonal treatment response and is associated with Gleason score and prostate cancer specific mortality. Eur J Cancer 48(4):538–546. doi:10.1016/j.ejca.2012.01.001

    Article  CAS  PubMed  Google Scholar 

  • Bismar TA, Alshalalfa M, Petersen LF, Teng LH, Gerke T, Bakkar A et al (2014) Interrogation of ERG gene rearrangements in prostate cancer identifies a prognostic 10-gene signature with relevant implication to patients’ clinical outcome. BJU Int 113(2):309–319. doi:10.1111/bju.12262

    Article  CAS  PubMed  Google Scholar 

  • Boormans JL, Hermans KG, Made AC, van Leenders GJ, Wildhagen MF, Collette L et al (2010) Expression of the androgen-regulated fusion gene TMPRSS2-ERG does not predict response to endocrine treatment in hormone-naive, node-positive prostate cancer. Eur Urol 57(5):830–835. doi:10.1016/j.eururo.2009.08.013

    Article  CAS  PubMed  Google Scholar 

  • Brase JC, Johannes M, Mannsperger H, Falth M, Metzger J, Kacprzyk LA et al (2011) TMPRSS2-ERG-specific transcriptional modulation is associated with prostate cancer biomarkers and TGF-beta signaling. BMC Cancer 11:507. doi:10.1186/1471-2407-11-507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brenner JC, Ateeq B, Li Y, Yocum AK, Cao Q, Asangani IA et al (2011) Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell 19(5):664–678. doi:10.1016/j.ccr.2011.04.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burdova A, Bouchal J, Tavandzis S, Kolar Z (2014) TMPRSS2-ERG gene fusion in prostate cancer. Biomed Pap 158(4):502–510. doi:10.5507/bp.2014.065

    Google Scholar 

  • Carver BS, Tran J, Gopalan A, Chen Z, Shaikh S, Carracedo A et al (2009) Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet 41(5):619–624. doi:10.1038/ng.370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaux A, Albadine R, Toubaji A, Hicks J, Meeker A, Platz EA et al (2011) Immunohistochemistry for ERG expression as a surrogate for TMPRSS2-ERG fusion detection in prostatic adenocarcinomas. Am J Surg Pathol 35(7):1014–1020. doi:10.1097/PAS.0b013e31821e8761

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen H, Nandi AK, Li X, Bieberich CJ (2002) NKX-3.1 interacts with prostate-derived Ets factor and regulates the activity of the PSA promoter. Cancer Res 62(2):338–340

    CAS  PubMed  Google Scholar 

  • Clark J, Merson S, Jhavar S, Flohr P, Edwards S, Foster CS et al (2007) Diversity of TMPRSS2-ERG fusion transcripts in the human prostate. Oncogene 26(18):2667–2673. doi:10.1038/sj.onc.1210070

    Article  CAS  PubMed  Google Scholar 

  • Dal Pra A, Lalonde E, Sykes J, Warde F, Ishkanian A, Meng A et al (2013) TMPRSS2-ERG status is not prognostic following prostate cancer radiotherapy: implications for fusion status and DSB repair. Clin Cancer Res 19(18):5202–5209. doi:10.1158/1078-0432.CCR-13-1049

    Article  CAS  PubMed  Google Scholar 

  • Darnel AD, Lafargue CJ, Vollmer RT, Corcos J, Bismar TA (2009) TMPRSS2-ERG fusion is frequently observed in Gleason pattern 3 prostate cancer in a Canadian cohort. Cancer Biol Ther 8(2):125–130

    Article  CAS  PubMed  Google Scholar 

  • Dasgupta S, Srinidhi S, Vishwanatha JK (2012) Oncogenic activation in prostate cancer progression and metastasis: molecular insights and future challenges. J Carcinog 11:4. doi:10.4103/1477-3163.93001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Demichelis F, Fall K, Perner S, Andren O, Schmidt F, Setlur SR et al (2007) TMPRSS2: ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 26(31):4596–4599. doi:10.1038/sj.onc.1210237

    Article  CAS  PubMed  Google Scholar 

  • Denmeade SR, Isaacs JT (2002) A history of prostate cancer treatment. Nat Rev Cancer 2(5):389–396. doi:10.1038/nrc801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Draisma G, Etzioni R, Tsodikov A, Mariotto A, Wever E, Gulati R et al (2009) Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context. J Natl Cancer Inst 101(6):374–383. doi:10.1093/jnci/djp001

    Article  PubMed  PubMed Central  Google Scholar 

  • Duterque-Coquillaud M, Niel C, Plaza S, Stehelin D (1993) New human erg isoforms generated by alternative splicing are transcriptional activators. Oncogene 8(7):1865–1873

    CAS  PubMed  Google Scholar 

  • Falzarano SM, Navas M, Simmerman K, Klein EA, Rubin MA, Zhou M et al (2010) ERG rearrangement is present in a subset of transition zone prostatic tumors. Mod Pathol 23(11):1499–1506. doi:10.1038/modpathol.2010.150

    Article  PubMed  Google Scholar 

  • Feldman BJ, Feldman D (2001) The development of androgen-independent prostate cancer. Nat Rev Cancer 1(1):34–45. doi:10.1038/35094009

    Article  CAS  PubMed  Google Scholar 

  • Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H et al (2013) Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 49(6):1374–1403. doi:10.1016/j.ejca.2012.12.027

    Article  CAS  PubMed  Google Scholar 

  • Fontugne J, Lee D, Cantaloni C, Barbieri CE, Caffo O, Hanspeter E et al (2014) Recurrent prostate cancer genomic alterations predict response to brachytherapy treatment. Cancer Epidemiol Biomarkers Prev 23(4):594–600. doi:10.1158/1055-9965.EPI-13-1180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franco OE, Hayward SW (2012) Targeting the tumor stroma as a novel therapeutic approach for prostate cancer. Adv Pharmacol 65:267–313. doi:10.1016/B978-0-12-397927-8.00009-9

    Article  CAS  PubMed  Google Scholar 

  • Furusato B, Tan SH, Young D, Dobi A, Sun C, Mohamed AA et al (2010) ERG oncoprotein expression in prostate cancer: clonal progression of ERG-positive tumor cells and potential for ERG-based stratification. Prostate Cancer Prostatic Dis 13(3):228–237. doi:10.1038/pcan.2010.23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gasi Tandefelt D, Boormans JL, van der Korput HA, Jenster GW, Trapman J (2013) A 36-gene signature predicts clinical progression in a subgroup of ERG-positive prostate cancers. Eur Urol 64(6):941–950. doi:10.1016/j.eururo.2013.02.039

    Article  CAS  PubMed  Google Scholar 

  • Gordanpour A, Stanimirovic A, Nam RK, Moreno CS, Sherman C, Sugar L et al (2011) miR-221 is down-regulated in TMPRSS2: ERG fusion-positive prostate cancer. Anticancer Res 31(2):403–410

    CAS  PubMed  PubMed Central  Google Scholar 

  • Grupp K, Kohl S, Sirma H, Simon R, Steurer S, Becker A et al (2013a) Cysteine-rich secretory protein 3 overexpression is linked to a subset of PTEN-deleted ERG fusion-positive prostate cancers with early biochemical recurrence. Mod Pathol 26(5):733–742. doi:10.1038/modpathol.2012.206

    Article  CAS  PubMed  Google Scholar 

  • Grupp K, Diebel F, Sirma H, Simon R, Breitmeyer K, Steurer S et al (2013b) SPINK1 expression is tightly linked to 6q15- and 5q21-deleted ERG-fusion negative prostate cancers but unrelated to PSA recurrence. Prostate 73(15):1690–1698. doi:10.1002/pros.22707

    CAS  PubMed  Google Scholar 

  • Guo CC, Dancer JY, Wang Y, Aparicio A, Navone NM, Troncoso P et al (2011) TMPRSS2-ERG gene fusion in small cell carcinoma of the prostate. Hum Pathol 42(1):11–17. doi:10.1016/j.humpath.2010.05.026

    Article  CAS  PubMed  Google Scholar 

  • Hagglof C, Hammarsten P, Stromvall K, Egevad L, Josefsson A, Stattin P et al (2014) TMPRSS2-ERG expression predicts prostate cancer survival and associates with stromal biomarkers. PLoS One 9(2):e86824. doi:10.1371/journal.pone.0086824

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Helgeson BE, Tomlins SA, Shah N, Laxman B, Cao Q, Prensner JR et al (2008) Characterization of TMPRSS2:ETV5 and SLC45A3: ETV5 gene fusions in prostate cancer. Cancer Res 68(1):73–80

    Article  CAS  PubMed  Google Scholar 

  • Hermans KG, van Marion R, van Dekken H, Jenster G, van Weerden WM, Trapman J (2006) TMPRSS2: ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptor-negative prostate cancer. Cancer Res 66(22):10658–10663. doi:10.1158/0008-5472.CAN-06-1871

    Article  CAS  PubMed  Google Scholar 

  • Hermans KG, van der Korput HA, van Marion R, van de Wijngaart DJ, Ziel-van der Made A, Dits NF et al (2008) Truncated ETV1, fused to novel tissue-specific genes, and full-length ETV1 in prostate cancer. Cancer Res 68(18):7541–7549. doi:10.1158/0008-5472.CAN-07-5930

    Article  CAS  PubMed  Google Scholar 

  • Hollenhorst PC, McIntosh LP, Graves BJ (2011) Genomic and biochemical insights into the specificity of ETS transcription factors. Annu Rev Biochem 80:437–471. doi:10.1146/annurev.biochem.79.081507.103945

    Article  CAS  PubMed  Google Scholar 

  • Hoogland AM, Jenster G, van Weerden WM, Trapman J, van der Kwast T, Roobol MJ et al (2012) ERG immunohistochemistry is not predictive for PSA recurrence, local recurrence or overall survival after radical prostatectomy for prostate cancer. Mod Pathol 25(3):471–479. doi:10.1038/modpathol.2011.176

    Article  CAS  PubMed  Google Scholar 

  • Huang KC, Dolph M, Donnelly B, Bismar TA (2014) ERG expression is associated with increased risk of biochemical relapse following radical prostatectomy in early onset prostate cancer. Clin Transl Oncol 16(11):973–979. doi:10.1007/s12094-014-1182-x

    Article  CAS  PubMed  Google Scholar 

  • Iljin K, Wolf M, Edgren H, Gupta S, Kilpinen S, Skotheim RI et al (2006) TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming. Cancer Res 66(21):10242–10246

    Article  CAS  PubMed  Google Scholar 

  • Kanazawa T, Ogawa C, Taketani T, Taki T, Hayashi Y, Morikawa A (2005) TLS/FUS-ERG fusion gene in acute lymphoblastic leukemia with t(16;21)(p11;q22) and monitoring of minimal residual disease. Leuk Lymphoma 46(12):1833–1835. doi:10.1080/10428190500162203

    Article  CAS  PubMed  Google Scholar 

  • Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW et al (2001) Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7(4):437–443. doi:10.1038/86507

    Article  PubMed  Google Scholar 

  • King JC, Xu J, Wongvipat J, Hieronymus H, Carver BS, Leung DH et al (2009) Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis. Nat Genet 41(5):524–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klezovitch O, Risk M, Coleman I, Lucas JM, Null M, True LD et al (2008) A causal role for ERG in neoplastic transformation of prostate epithelium. Proc Natl Acad Sci USA 105(6):2105–2110. doi:10.1073/pnas.0711711105

    Article  PubMed  PubMed Central  Google Scholar 

  • Kron K, Trudel D, Pethe V, Briollais L, Fleshner N, van der Kwast T et al (2013) Altered DNA methylation landscapes of polycomb-repressed loci are associated with prostate cancer progression and ERG oncogene expression in prostate cancer. Clin Cancer Res 19(13):3450–3461. doi:10.1158/1078-0432.CCR-12-3139

    Article  CAS  PubMed  Google Scholar 

  • Kumar-Sinha C, Tomlins SA, Chinnaiyan AM (2008) Recurrent gene fusions in prostate cancer. Nat Rev Cancer 8(7):497–511. doi:10.1038/nrc2402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee SL, Yu D, Wang C, Saba R, Liu S, Trpkov K et al (2014) ERG expression in prostate needle biopsy: potential diagnostic and prognostic implications. Appl Immunohistochem Mol Morphol. doi:10.1097/PAI.0000000000000119

    PubMed  Google Scholar 

  • Lee SL, Yu D, Wang C, Saba R, Liu S, Trpkov K et al (2015) ERG expression in prostate needle biopsy: potential diagnostic and prognostic implications. Appl Immunohistochem Mol Morphol 23(7):499–505. doi:10.1097/PAI.0000000000000119

    Article  CAS  PubMed  Google Scholar 

  • Leinonen KA, Tolonen TT, Bracken H, Stenman UH, Tammela TL, Saramaki OR et al (2010) Association of SPINK1 expression and TMPRSS2: ERG fusion with prognosis in endocrine-treated prostate cancer. Clin Cancer Res 16(10):2845–2851. doi:10.1158/1078-0432.CCR-09-2505

    Article  CAS  PubMed  Google Scholar 

  • Leinonen KA, Saramäki OR, Furusato B, Kimura T, Takahashi H, Egawa S et al (2013) Loss of PTEN is associated with aggressive behavior in ERG-positive prostate cancer. Cancer Epidemiol Biomarkers Prev 22(12):2333–2344. doi:10.1158/1055-9965.epi-13-0333-t

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leyten GH, Hessels D, Jannink SA, Smit FP, de Jong H, Cornel EB et al (2014) Prospective multicentre evaluation of PCA3 and TMPRSS2-ERG gene fusions as diagnostic and prognostic urinary biomarkers for prostate cancer. Eur Urol 65(3):534–542. doi:10.1016/j.eururo.2012.11.014

    Article  CAS  PubMed  Google Scholar 

  • Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI et al (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275(5308):1943–1947

    Article  CAS  PubMed  Google Scholar 

  • Liu S, Yoshimoto M, Trpkov K, Duan Q, Firszt M, Corcos J et al (2011) Detection of ERG gene rearrangements and PTEN deletions in unsuspected prostate cancer of the transition zone. Cancer Biol Ther 11(6):562–566

    Article  PubMed  Google Scholar 

  • Locke JA, Zafarana G, Ishkanian AS, Milosevic M, Thoms J, Have CL et al (2012) NKX3.1 haploinsufficiency is prognostic for prostate cancer relapse following surgery or image-guided radiotherapy. Clin Cancer Res 18(1):308–316. doi:10.1158/1078-0432.CCR-11-2147

    Article  CAS  PubMed  Google Scholar 

  • Lotan TL, Gupta NS, Wang W, Toubaji A, Haffner MC, Chaux A et al (2011) ERG gene rearrangements are common in prostatic small cell carcinomas. Mod Pathol 24(6):820–828. doi:10.1038/modpathol.2011.7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loughran SJ, Kruse EA, Hacking DF, de Graaf CA, Hyland CD, Willson TA et al (2008) The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells. Nat Immunol 9(7):810–819. doi:10.1038/ni.1617

    Article  CAS  PubMed  Google Scholar 

  • Mahdian R, Nodouzi V, Asgari M, Rezaie M, Alizadeh J, Yousefi B et al (2014) Expression profile of MAGI2 gene as a novel biomarker in combination with major deregulated genes in prostate cancer. Mol Biol Rep 41(9):6125–6131. doi:10.1007/s11033-014-3491-0

    Article  CAS  PubMed  Google Scholar 

  • Mani RS, Tomlins SA, Callahan K, Ghosh A, Nyati MK, Varambally S et al (2009) Induced chromosomal proximity and gene fusions in prostate cancer. Science 326(5957):1230. doi:10.1126/science.1178124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mehra R, Tomlins SA, Shen R, Nadeem O, Wang L, Wei JT et al (2007) Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Mod Pathol 20(5):538–544. doi:10.1038/modpathol.3800769

    Article  CAS  PubMed  Google Scholar 

  • Mertz KD, Setlur SR, Dhanasekaran SM, Demichelis F, Perner S, Tomlins S et al (2007) Molecular characterization of TMPRSS2-ERG gene fusion in the NCI-H660 prostate cancer cell line: a new perspective for an old model. Neoplasia 9(3):200–206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miettinen M, Wang ZF, Paetau A, Tan SH, Dobi A, Srivastava S et al (2011) ERG transcription factor as an immunohistochemical marker for vascular endothelial tumors and prostatic carcinoma. Am J Surg Pathol 35(3):432–441. doi:10.1097/PAS.0b013e318206b67b

    Article  PubMed  Google Scholar 

  • Minner S, Enodien M, Sirma H, Luebke AM, Krohn A, Mayer PS et al (2011) ERG status is unrelated to PSA recurrence in radically operated prostate cancer in the absence of antihormonal therapy. Clin Cancer Res 17(18):5878–5888. doi:10.1158/1078-0432.CCR-11-1251

    Article  CAS  PubMed  Google Scholar 

  • Mochmann LH, Neumann M, von der Heide EK, Nowak V, Kuhl AA, Ortiz-Tanchez J et al (2014) ERG induces a mesenchymal-like state associated with chemoresistance in leukemia cells. Oncotarget 5(2):351–362

    Article  PubMed  Google Scholar 

  • Mohamed AA, Tan SH, Sun C, Shaheduzzaman S, Hu Y, Petrovics G et al (2011) ERG oncogene modulates prostaglandin signaling in prostate cancer cells. Cancer Biol Ther 11(4):410–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mosquera JM, Perner S, Genega EM, Sanda M, Hofer MD, Mertz KD et al (2008) Characterization of TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications. Clin Cancer Res 14(11):3380–3385. doi:10.1158/1078-0432.CCR-07-5194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD et al (2007) Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446(7137):758–764. doi:10.1038/nature05690

    Article  CAS  PubMed  Google Scholar 

  • Nagle RB, Algotar AM, Cortez CC, Smith K, Jones C, Sathyanarayana UG et al (2013) ERG overexpression and PTEN status predict capsular penetration in prostate carcinoma. Prostate 73(11):1233–1240. doi:10.1002/pros.22675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nam RK, Sugar L, Wang Z, Yang W, Kitching R, Klotz LH et al (2007a) Expression of TMPRSS2: ERG gene fusion in prostate cancer cells is an important prognostic factor for cancer progression. Cancer Biol Ther 6(1):40–45

    Article  CAS  PubMed  Google Scholar 

  • Nam RK, Sugar L, Yang W, Srivastava S, Klotz LH, Yang LY et al (2007b) Expression of the TMPRSS2: ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer. Br J Cancer 97(12):1690–1695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ng HH, Bird A (2000) Histone deacetylases: silencers for hire. Trends Biochem Sci 25(3):121–126

    Article  CAS  PubMed  Google Scholar 

  • Oh SH, Park TS, Choi JR, Lee S, Cho SY, Kim SY et al (2010) Two childhood cases of acute leukemia with t(16;21)(p11.2;q22): second case report of infantile acute lymphoblastic leukemia with unusual type of FUS-ERG chimeric transcript. Cancer Genet Cytogenet 200(2):180–183. doi:10.1016/j.cancergencyto.2010.04.009

    Article  CAS  PubMed  Google Scholar 

  • Owczarek CM, Portbury KJ, Hardy MP, O’Leary DA, Kudoh J, Shibuya K et al (2004) Detailed mapping of the ERG–ETS2 interval of human chromosome 21 and comparison with the region of conserved synteny on mouse chromosome 16. Gene 324:65–77

    Article  CAS  PubMed  Google Scholar 

  • Park K, Tomlins SA, Mudaliar KM, Chiu YL, Esgueva R, Mehra R et al (2010) Antibody-based detection of ERG rearrangement-positive prostate cancer. Neoplasia 12(7):590–598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park K, Dalton JT, Narayanan R, Barbieri CE, Hancock ML, Bostwick DG et al (2014) TMPRSS2: ERG gene fusion predicts subsequent detection of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia. J Clin Oncol 32(3):206–211. doi:10.1200/JCO.2013.49.8386

    Article  PubMed  Google Scholar 

  • Perner S, Demichelis F, Beroukhim R, Schmidt FH, Mosquera JM, Setlur S et al (2006) TMPRSS2: ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res 66(17):8337–8341

    Article  CAS  PubMed  Google Scholar 

  • Petrovics G, Liu A, Shaheduzzaman S, Furusato B, Sun C, Chen Y et al (2005) Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome. Oncogene 24(23):3847–3852. doi:10.1038/sj.onc.1208518

    Article  CAS  PubMed  Google Scholar 

  • Pflueger D, Rickman DS, Sboner A, Perner S, LaFargue CJ, Svensson MA et al (2009) N-myc downstream regulated gene 1 (NDRG1) is fused to ERG in prostate cancer. Neoplasia 11(8):804–811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rajan P, Stockley J, Sudbery IM, Fleming JT, Hedley A, Kalna G et al (2014) Identification of a candidate prognostic gene signature by transcriptome analysis of matched pre- and post-treatment prostatic biopsies from patients with advanced prostate cancer. BMC Cancer 14:977. doi:10.1186/1471-2407-14-977

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rao VN, Papas TS, Reddy ES (1987) erg, a human ets-related gene on chromosome 21: alternative splicing, polyadenylation, and translation. Science 237(4815):635–639

    Article  CAS  PubMed  Google Scholar 

  • Rao VN, Modi WS, Drabkin HD, Patterson D, O’Brien SJ, Papas TS et al (1988) The human erg gene maps to chromosome 21, band q22: relationship to the 8; 21 translocation of acute myelogenous leukemia. Oncogene 3(5):497–500

    CAS  PubMed  Google Scholar 

  • Reddy ES, Rao VN, Papas TS (1987) The erg gene: a human gene related to the ets oncogene. Proc Natl Acad Sci U S A 84(17):6131–6135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ribeiro FR, Paulo P, Costa VL, Barros-Silva JD, Ramalho-Carvalho J, Jeronimo C et al (2011) Cysteine-rich secretory protein-3 (CRISP3) is strongly up-regulated in prostate carcinomas with the TMPRSS2-ERG fusion gene. PLoS One 6(7):e22317. doi:10.1371/journal.pone.0022317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ropero S, Esteller M (2007) The role of histone deacetylases (HDACs) in human cancer. Mol Oncol 1(1):19–25. doi:10.1016/j.molonc.2007.01.001

    Article  CAS  PubMed  Google Scholar 

  • Ross LE, Berkowitz Z, Ekwueme DU (2008) Use of the prostate-specific antigen test among U.S. men: findings from the 2005 National Health Interview Survey. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive. Oncology 17(3):636–644. doi:10.1158/1055-9965.EPI-07-2709

    Google Scholar 

  • Setlur SR, Mertz KD, Hoshida Y, Demichelis F, Lupien M, Perner S et al (2008) Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. J Natl Cancer Inst 100(11):815–825. doi:10.1093/jnci/djn150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shah RB (2013) Clinical applications of novel ERG immunohistochemistry in prostate cancer diagnosis and management. Adv Anat Pathol 20(2):117–124. doi:10.1097/PAP.0b013e3182862ac5

    Article  CAS  PubMed  Google Scholar 

  • Shah RB, Tadros Y, Brummell B, Zhou M (2013) The diagnostic use of ERG in resolving an “atypical glands suspicious for cancer” diagnosis in prostate biopsies beyond that provided by basal cell and alpha-methylacyl-CoA-racemase markers. Hum Pathol 44(5):786–794. doi:10.1016/j.humpath.2012.06.024

    Article  CAS  PubMed  Google Scholar 

  • Sharrocks AD (2001) The ETS-domain transcription factor family. Nat Rev Mol Cell Biol 2(11):827–837. doi:10.1038/35099076

    Article  CAS  PubMed  Google Scholar 

  • Shimizu K, Ichikawa H, Tojo A, Kaneko Y, Maseki N, Hayashi Y et al (1993) An ets-related gene, ERG, is rearranged in human myeloid leukemia with t(16;21) chromosomal translocation. Proc Natl Acad Sci U S A 90(21):10280–10284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63(1):11–30. doi:10.3322/caac.21166

    Article  PubMed  Google Scholar 

  • Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29. doi:10.3322/caac.21254

    Article  PubMed  Google Scholar 

  • Slovin SF, Kelly WK, Wilton A, Kattan M, Myskowski P, Mendelsohn J et al (2009) Anti-epidermal growth factor receptor monoclonal antibody cetuximab plus Doxorubicin in the treatment of metastatic castration-resistant prostate cancer. Clin Genitourin Cancer 7(3):E77–E82. doi:10.3816/CGC.2009.n.028

    Article  CAS  PubMed  Google Scholar 

  • Sorensen PH, Lessnick SL, Lopez-Terrada D, Liu XF, Triche TJ, Denny CT (1994) A second Ewing’s sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nat Genet 6(2):146–151. doi:10.1038/ng0294-146

    Article  CAS  PubMed  Google Scholar 

  • Spencer ES, Johnston RB, Gordon RR, Lucas JM, Ussakli CH, Hurtado-Coll A et al (2013) Prognostic value of ERG oncoprotein in prostate cancer recurrence and cause-specific mortality. Prostate 73(9):905–912. doi:10.1002/pros.22636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steurer S, Mayer PS, Adam M, Krohn A, Koop C, Ospina-Klinck D et al (2014) TMPRSS2-ERG fusions are strongly linked to young patient age in low-grade prostate cancer. Eur Urol 66(6):978–981. doi:10.1016/j.eururo.2014.06.027

    Article  CAS  PubMed  Google Scholar 

  • Sun C, Dobi A, Mohamed A, Li H, Thangapazham RL, Furusato B et al (2008) TMPRSS2-ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation. Oncogene 27(40):5348–5353. doi:10.1038/onc.2008.183

    Article  CAS  PubMed  Google Scholar 

  • Svensson MA, Perner S, Ohlson AL, Day JR, Groskopf J, Kirsten R et al (2014) A comparative study of ERG status assessment on DNA, mRNA, and protein levels using unique samples from a Swedish biopsy cohort. Appl Immunohistochem Mol Morphol 22(2):136–141. doi:10.1097/PDM.0b013e31829e0484

    Article  CAS  PubMed  Google Scholar 

  • Teng LH, Wang C, Dolph M, Donnelly B, Bismar TA (2013) ERG protein expression is of limited prognostic value in men with localized prostate cancer. ISRN Urol 2013:786545. doi:10.1155/2013/786545

    PubMed  PubMed Central  Google Scholar 

  • Terry S, Nicolaiew N, Basset V, Semprez F, Soyeux P, Maille P et al (2015) Clinical value of ERG, TFF3, and SPINK1 for molecular subtyping of prostate cancer. Cancer. doi:10.1002/cncr.29233

    Google Scholar 

  • Thangapazham R, Saenz F, Katta S, Mohamed AA, Tan SH, Petrovics G et al (2014) Loss of the NKX3.1 tumorsuppressor promotes the TMPRSS2-ERG fusion gene expression in prostate cancer. BMC Cancer 14:16. doi:10.1186/1471-2407-14-16

    Article  PubMed  PubMed Central  Google Scholar 

  • Tian TV, Tomavo N, Huot L, Flourens A, Bonnelye E, Flajollet S et al (2014) Identification of novel TMPRSS2: ERG mechanisms in prostate cancer metastasis: involvement of MMP9 and PLXNA2. Oncogene 33(17):2204–2214. doi:10.1038/onc.2013.176

    Article  CAS  PubMed  Google Scholar 

  • Tidehag V, Hammarsten P, Egevad L, Granfors T, Stattin P, Leanderson T et al (2014) High density of S100A9 positive inflammatory cells in prostate cancer stroma is associated with poor outcome. Eur J Cancer 50(10):1829–1835. doi:10.1016/j.ejca.2014.03.278

    Article  CAS  PubMed  Google Scholar 

  • Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW et al (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310(5748):644–648

    Article  CAS  PubMed  Google Scholar 

  • Tomlins SA, Alshalalfa M, Davicioni E, Erho N, Yousefi K, Zhao S et al (2015a) Characterization of 1577 primary prostate cancers reveals novel biological and clinicopathologic insights into molecular subtypes. Eur Urol 68(4):555–567. doi:10.1016/j.eururo.2015.04.033

    Article  PubMed  Google Scholar 

  • Tomlins SA, Day JR, Lonigro RJ, Hovelson DH, Siddiqui J, Kunju LP et al (2015b) Urine TMPRSS2: ERG plus PCA3 for individualized prostate cancer risk assessment. Eur Urol. doi:10.1016/j.eururo.2015.04.039

    Google Scholar 

  • Toubaji A, Albadine R, Meeker AK, Isaacs WB, Lotan T, Haffner MC et al (2011) Increased gene copy number of ERG on chromosome 21 but not TMPRSS2-ERG fusion predicts outcome in prostatic adenocarcinomas. Mod Pathol 24(11):1511–1520. doi:10.1038/modpathol.2011.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Leenders GJ, Boormans JL, Vissers CJ, Hoogland AM, Bressers AA, Furusato B et al (2011) Antibody EPR3864 is specific for ERG genomic fusions in prostate cancer: implications for pathological practice. Mod Pathol 24(8):1128–1138. doi:10.1038/modpathol.2011.65

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Cai Y, Ren C, Ittmann M (2006) Expression of variant TMPRSS2/ERG fusion messenger RNAs is associated with aggressive prostate cancer. Cancer Res 66(17):8347–8351. doi:10.1158/0008-5472.CAN-06-1966

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Cai Y, Yu W, Ren C, Spencer DM, Ittmann M (2008) Pleiotropic biological activities of alternatively spliced TMPRSS2/ERG fusion gene transcripts. Cancer Res 68(20):8516–8524. doi:10.1158/0008-5472.CAN-08-1147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang JJ, Liu YX, Wang W, Yan W, Zheng YP, Qiao LD et al (2012) Fusion between TMPRSS2 and ETS family members (ERG, ETV1, ETV4) in prostate cancers from northern China. Asian Pac J Cancer Prev 13(10):4935–4938

    Article  PubMed  Google Scholar 

  • Wilson S, Greer B, Hooper J, Zijlstra A, Walker B, Quigley J et al (2005) The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells. Biochem J 388(Pt 3):967–972. doi:10.1042/BJ20041066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yaskiv O, Zhang X, Simmerman K, Daly T, He H, Falzarano S et al (2011) The utility of ERG/P63 double immunohistochemical staining in the diagnosis of limited cancer in prostate needle biopsies. Am J Surg Pathol 35(7):1062–1068. doi:10.1097/PAS.0b013e318215cc03

    Article  PubMed  Google Scholar 

  • Yoshimoto M, Joshua AM, Cunha IW, Coudry RA, Fonseca FP, Ludkovski O et al (2008) Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome. Mod Pathol 21(12):1451–1460. doi:10.1038/modpathol.2008.96

    Article  CAS  PubMed  Google Scholar 

  • Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X et al (2010) An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Cancer Cell 17(5):443–454. doi:10.1016/j.ccr.2010.03.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

LZ and TAB drafted the manuscript. TAB supervised and oversight the manuscript outline.

Funding

This work was supported in part by the Prostate Cancer Foundation Young Investigator Award (T.A.B). This work was also supported by Prostate cancer Canada and is proudly funded by the Movember Foundation, Grant #B2013-01.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, Canada

    Hatem Abou-Ouf, Liena Zhao & Tarek A. Bismar

  2. Departments of Oncology, Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada

    Tarek A. Bismar

  3. Arnie Charbonneau Cancer Institute and Tom Baker Cancer Center, Calgary, AB, Canada

    Hatem Abou-Ouf & Tarek A. Bismar

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  1. Hatem Abou-Ouf
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  2. Liena Zhao
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  3. Tarek A. Bismar
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Correspondence to Tarek A. Bismar.

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Abou-Ouf, H., Zhao, L. & Bismar, T.A. ERG expression in prostate cancer: biological relevance and clinical implication. J Cancer Res Clin Oncol 142, 1781–1793 (2016). https://doi.org/10.1007/s00432-015-2096-x

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