Journal of Cancer Research and Clinical Oncology

, Volume 145, Issue 7, pp 1751–1759 | Cite as

Combined loss of TFF3 and PTEN is associated with lethal outcome and overall survival in men with prostate cancer

  • Hatem Abou-Ouf
  • Sunita Ghosh
  • Adrian Box
  • Nallasivam Palanisamy
  • Tarek A. BismarEmail author
Original Article – Cancer Research



Trefoil Factor 3 (TFF3) has been implicated in Prostate Cancer (PCa) progression. However, its prognostic value and association with other biomarkers have not been fully explored. We assessed the combined value of TFF3 and PTEN in two cohorts: one is managed surgically for localized PCa and the second is managed non-surgically by androgen deprivation therapy for advanced disease.


228 radical prostatectomies (RP) and 318 transurethral resection of prostate (TURP) samples were assessed by immunohistochemistry (IHC) for TFF3 and by IHC and fluorescent in situ hybridization (FISH) for PTEN. Results of biomarkers expression were correlated with various pathological and clinical outcome parameters including biochemical recurrence (BCR) in the RP cohort and cancer-specific mortality (PCSM) and overall survival (OS) in the TURP cohort.


TFF3 expression was detected in 131/226 (57.9%) RP samples and 148/318 (46.5%) of TURP cases. In general, TFF3 positivity was less frequently observed with advanced Gleason Groups. TFF3 expression was also assessed in relation to PTEN expression. Only 15–16% of TFF3-expressed cases were present in association with complete loss of PTEN expression in the TURP and localized cohorts, respectively. Loss of TFF3 expression was not related to BCR after RP, but was prognostic in the non-surgical cohort and associated with decrease OS and PCSM (HR 2.31, CI: 1.67–3.18, p < 0.0001) and (HR 3.99, CI: 2.43–6.56; p < 0.0001), respectively. Adjusting for Gleason score, combined loss of TFF3/PTEN was most associated with OS (HR 2.33, CI: 1.49–3.62; p < 0.0001) and PCSM (HR = 3.44, CI: 1.75–6.78, p < 0.0001).


The study documents for the first time significant association for combined status of TFF3 expression and PTEN loss in OS and PCSM in patients not managed by surgical intervention. Prospective assessment of PTEN and TFF3 may provide further insight into molecularly subtyping PCa and aid in stratifying patients at risk for lethal disease.


TFF3 PTEN Protein expression Immunohistochemistry Gleason score Androgen deprivation therapy Cancer specific mortality Biochemical recurrence 



The study was supported in part by the Prostate Cancer Foundation Young Investigator Award (T.A.B). This work is also supported by Prostate cancer Canada and is proudly funded by the Movember Foundation-Grant#B2013-01 and Funds from Ride for Dads (TAB). The authors would like to thank Mrs. Ruby Reyes for technical support in this manuscript.

Compliance with ethical standards

The study was approved by the U Calgary Cumming School of Medicine ethics review board and in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

432_2019_2933_MOESM1_ESM.tiff (213 kb)
Supplementary file1 (TIFF 213 kb)


  1. Abou-Ouf H, Zhao L, Bismar TA (2016) ERG expression in prostate cancer: biological relevance and clinical implication. J Cancer Res Clin Oncol 142:1781–1793. CrossRefGoogle Scholar
  2. Bismar TA, Yoshimoto M, Vollmer RT, Duan Q, Firszt M, Corcos J, Squire JA (2011) PTEN genomic deletion is an early event associated with ERG gene rearrangements in prostate cancer. BJU Int 107:477–485. CrossRefGoogle Scholar
  3. Bismar TA, Dolph M, Teng LH, Liu S, Donnelly B (2012a) ERG protein expression reflects hormonal treatment response and is associated with Gleason score and prostate cancer specific mortality. Eur J Cancer 48:538–546. CrossRefGoogle Scholar
  4. Bismar TA, Yoshimoto M, Duan Q, Liu S, Sircar K, Squire JA (2012b) Interactions and relationships of PTEN, ERG, SPINK1 and AR in castration-resistant prostate cancer. Histopathology 60:645–652. CrossRefGoogle Scholar
  5. Bismar TA, Hegazy S, Feng Z, Yu D, Donnelly B, Palanisamy N, Trock BJ (2018) Clinical utility of assessing PTEN and ERG protein expression in prostate cancer patients: a proposed method for risk stratification. J Cancer Res Clin Oncol 25:46. Google Scholar
  6. Dal Pra A, Lalonde E, Sykes J, Warde F, Ishkanian A, Meng A, Maloff C, Srigley J, Joshua AM, Petrovics G, van der Kwast T, Evans A, Milosevic M, Saad F, Collins C, Squire J, Lam W, Bismar TA, Boutros PC, Bristow RG (2013) TMPRSS2-ERG status is not prognostic following prostate cancer radiotherapy: implications for fusion status and DSB repair. Clin Cancer Res 19:5202–5209. CrossRefGoogle Scholar
  7. Demichelis F, Fall K, Perner S, Andren O, Schmidt F, Setlur SR, Hoshida Y, Mosquera JM, Pawitan Y, Lee C, Adami HO, Mucci LA, Kantoff PW, Andersson SO, Chinnaiyan AM, Johansson JE, Rubin MA (2007) TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 26:4596–4599. CrossRefGoogle Scholar
  8. Hoogland AM, Jenster G, van Weerden WM, Trapman J, van der Kwast T, Roobol MJ, Schroder FH, Wildhagen MF, van Leenders GJ (2012) ERG immunohistochemistry is not predictive for PSA recurrence, local recurrence or overall survival after radical prostatectomy for prostate cancer. Mod Pathol 25:471–479. CrossRefGoogle Scholar
  9. Huang KC, Alshalalfa M, Hegazy SA, Dolph M, Donnelly B, Bismar TA (2014a) The prognostic significance of combined ERG and androgen receptor expression in patients with prostate cancer managed by androgen deprivation therapy. Cancer Biol Ther 15:1120–1128. CrossRefGoogle Scholar
  10. Huang KC, Dolph M, Donnelly B, Bismar TA (2014b) ERG expression is associated with increased risk of biochemical relapse following radical prostatectomy in early onset prostate cancer. Clin Transl Oncol 16:973–979. CrossRefGoogle Scholar
  11. Huang KC, Begin LR, Palanisamy N, Donnelly B, Bismar TA (2016) SPINK1 expression in relation to PTEN and ERG in matched primary and lymph node metastatic prostate cancer: Implications for biomarker development. Urol Oncol 34(235):e231–210. Google Scholar
  12. Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, Zhang J, Signoretti S, Loda M, Roberts TM, Zhao JJ (2008) Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454:776–779. CrossRefGoogle Scholar
  13. Johansson JE, Andren O, Andersson SO, Dickman PW, Holmberg L, Magnuson A, Adami HO (2004) Natural history of early, localized prostate cancer. JAMA 291(22):2713–2719CrossRefGoogle Scholar
  14. Lee SH, Poulogiannis G, Pyne S, Jia S, Zou L, Signoretti S, Loda M, Cantley LC, Roberts TM (2010) A constitutively activated form of the p110beta isoform of PI3-kinase induces prostatic intraepithelial neoplasia in mice. Proc Natl Acad Sci USA 107:11002–11007. CrossRefGoogle Scholar
  15. Lee SL, Yu D, Wang C, Saba R, Liu S, Trpkov K, Donnelly B, Bismar TA (2015) ERG expression in prostate needle biopsy: potential diagnostic and prognostic implications. Appl Immunohistochem Mol Morphol 23:499–505. CrossRefGoogle Scholar
  16. Liu S, Yoshimoto M, Trpkov K, Duan Q, Firszt M, Corcos J, Squire JA, Bismar TA (2011) Detection of ERG gene rearrangements and PTEN deletions in unsuspected prostate cancer of the transition zone. Cancer Biol Ther 11:562–566CrossRefGoogle Scholar
  17. Matsui S, Simon R, Qu P, Shaughnessy JD Jr, Barlogie B, Crowley J (2012) Developing and validating continuous genomic signatures in randomized clinical trials for predictive medicine. Clin Cancer Res 18:6065–6073. CrossRefGoogle Scholar
  18. Reid AH, Attard G, Ambroisine L, Fisher G, Kovacs G, Brewer D, Clark J, Flohr P, Edwards S, Berney DM, Foster CS, Fletcher A, Gerald WL, Moller H, Reuter VE, Scardino PT, Cuzick J, de Bono JS, Cooper CS (2010) Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer. Br J Cancer 102:678–684. CrossRefGoogle Scholar
  19. Rickman DS, Chen YB, Banerjee S, Pan Y, Yu J, Vuong T, Perner S, Lafargue CJ, Mertz KD, Setlur SR, Sircar K, Chinnaiyan AM, Bismar TA, Rubin MA, Demichelis F (2010) ERG cooperates with androgen receptor in regulating trefoil factor 3 in prostate cancer disease progression. Neoplasia 12:1031–1040CrossRefGoogle Scholar
  20. Sircar K, Yoshimoto M, Monzon FA, Koumakpayi IH, Katz RL, Khanna A, Alvarez K, Chen G, Darnel AD, Aprikian AG, Saad F, Bismar TA, Squire JA (2009) PTEN genomic deletion is associated with p-Akt and AR signalling in poorer outcome, hormone refractory prostate cancer. J Pathol 218:505–513. CrossRefGoogle Scholar
  21. Teng LH, Wang C, Begin LR, Dolph M, Yilmaz A, Trpkov K, Donnelly B, Bismar TA (2013a) ERG protein expression and gene rearrangements are present at lower rates in metastatic and locally advanced castration-resistant prostate cancer compared to localized disease. Urology 82:394–399. CrossRefGoogle Scholar
  22. Teng LH, Wang C, Dolph M, Donnelly B, Bismar TA (2013b) ERG protein expression is of limited prognostic value in men with localized prostate cancer. ISRN Urol 2013:786545. Google Scholar
  23. Tomlins SA, Palanisamy N, Siddiqui J, Chinnaiyan AM, Kunju LP (2012) Antibody-based detection of ERG rearrangements in prostate core biopsies, including diagnostically challenging cases: ERG staining in prostate core biopsies. Arch Pathol Lab Med 136:935–946. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineUniversity of Calgary Cumming School of Medicine and Calgary Laboratory ServicesCalgaryCanada
  2. 2.Department of Medical Oncology, Faculty of Medicine and DentistryUniversity of AlbertaEdmontonCanada
  3. 3.Department of UrologyVattikuti Urology Institute, Henry Ford Health System DetroitDetroitUSA
  4. 4.Department of OncologyUniversity of Calgary Cumming School of MedicineCalgaryCanada
  5. 5.Department of Biochemistry and Molecular BiologyUniversity of Calgary Cumming School of MedicineCalgaryCanada
  6. 6.Arnie Charbonneau Cancer Institute and Tom Baker Cancer CenterCalgaryCanada

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