Skip to main content

Advertisement

SpringerLink
Log in

Prognostic significance of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in patients with breast cancer

  • Original Articles
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis upon binding to TRAIL receptors 1 and 2 (TRAIL-R1/DR4 and TRAIL-R2/DR5). TRAIL-R3 (DcR1) and TRAIL-R4 (DcR2) have no or only a truncated cytoplasmic death domain. Consequently, they cannot induce apoptosis and instead have been proposed to inhibit apoptosis induction by TRAIL. Agonists for the apoptosis-inducing TRAIL-R1 and TRAIL-R2 are currently tested in clinical trials. To determine the expression pattern of all surface-bound TRAIL receptors and their prognostic clinical value, we investigated tumour samples of 311 patients with breast cancer by immunohistochemistry. TRAIL receptor expression profiles were correlated with clinico-pathological data, disease-free survival and overall survival. TRAIL-R1 was more strongly expressed in better differentiated tumours, and correlated positively with surrogate markers of a better prognosis (hormone receptor status, Bcl-2, negative nodal status), but negatively with the expression of Her2/neu and the proliferation marker Ki67. In contrast, TRAIL-R2 and TRAIL-R4 expression correlated with higher tumour grades, higher Ki67 index, higher Her2/neu expression and a positive nodal status at the time of diagnosis, but with lower expression of Bcl-2. Thus, the TRAIL receptor expression pattern was predictive of nodal status. Patients with grade 1 and 2 tumours, who had TRAIL-R2 but no TRAIL-R1, showed a positive lymph node status in 47% of the cases. Vice versa, only 19% had a positive nodal status with high TRAIL-R1 but low TRAIL-R2. Most strikingly, TRAIL-R4 and -R2 expression negatively correlated with overall survival of breast cancer patients. Although TRAIL-R2 correlated with more aggressive tumour behaviour, mammary carcinoma could be sensitised to TRAIL-R2-induced apoptosis, suggesting that TRAIL-R2 might therefore be used to therapeutically target such tumours. Hence, determination of the TRAIL receptor expression profile may aid in defining which breast cancer patients have a higher risk of lymph node metastasis and worse overall survival and on the other hand will help to guide TRAIL-based tumour therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

Bio-LZ-TRAIL:

Biotinylated LZ-TRAIL

DD:

Death domain

DED:

Death effector domain

DFS:

Disease-free survival

DISC:

Death-inducing signalling complex

ER:

Estrogen receptor

FADD:

Fas-associated death domain protein

GPI:

Glycosyl-phospatidylinositol

HCC:

Hepatocellular carcinoma

Her2/neu:

Human epidermal growth factor receptor 2 oncogene

NSCLC:

Non-small cell lung cancer

PgR:

Progesterone receptor

OS:

Overall survival

TNF:

Tumour necrosis factor

TRAIL:

TNF-related apoptosis-inducing ligand

References

  1. Baetu TM, Hiscott J (2002) On the TRAIL to apoptosis. Cytokine Growth Factor Rev 13:199–207

    Article  CAS  PubMed  Google Scholar 

  2. Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J, Hood L (1997) Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway. Immunity 7:821–830

    Article  CAS  PubMed  Google Scholar 

  3. Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J et al (1997) The receptor for the cytotoxic ligand TRAIL. Science 276:111–113

    Article  CAS  PubMed  Google Scholar 

  4. Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N et al (1997) TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. EMBO J 16:5386–5397

    Article  CAS  PubMed  Google Scholar 

  5. Degli-Esposti MA, Dougall WC, Smolak PJ, Waugh JY, Smith CA, Goodwin RG (1997) The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 7:813–820

    Article  CAS  PubMed  Google Scholar 

  6. Degli-Esposti MA, Smolak PJ, Walczak H, Waugh J, Huang CP, DuBose RF et al (1997) Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family. J Exp Med 186:1165–1170

    Article  CAS  PubMed  Google Scholar 

  7. Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D et al (1997) Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277:818–821

    Article  CAS  PubMed  Google Scholar 

  8. Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C et al (1998) Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 273:14363–14367

    Article  CAS  PubMed  Google Scholar 

  9. Ganten TM, Koschny R, Haas TL, Sykora J, Li-Weber M, Herzer K et al (2005) Proteasome inhibition sensitizes hepatocellular carcinoma cells, but not human hepatocytes, to TRAIL. Hepatology 42:588–597

    Article  CAS  PubMed  Google Scholar 

  10. Ganten TM, Koschny R, Sykora J, Schulze-Bergkamen H, Buchler P, Haas TL et al (2006) Preclinical differentiation between apparently safe and potentially hepatotoxic applications of TRAIL either alone or in combination with chemotherapeutic drugs. Clin Cancer Res 12:2640–2646

    Article  CAS  PubMed  Google Scholar 

  11. Wajant H, Gerspach J, Pfizenmaier K (2005) Tumour therapeutics by design: targeting and activation of death receptors. Cytokine Growth Factor Rev 16:55–76

    Article  CAS  PubMed  Google Scholar 

  12. Yamamoto T, Nagano H, Sakon M, Wada H, Eguchi H, Kondo M et al (2004) Partial contribution of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumour effects of interferon-alpha/5-fluorouracil against hepatocellular carcinoma. Clin Cancer Res 10:7884–7895

    Article  CAS  PubMed  Google Scholar 

  13. Chen XP, He SQ, Wang HP, Zhao YZ, Zhang WG (2003) Expression of TNF-related apoptosis-inducing ligand receptors and antitumour tumour effects of TNF-related apoptosis-inducing ligand in human hepatocellular carcinoma. World J Gastroenterol 9:2433–2440

    CAS  PubMed  Google Scholar 

  14. Strater J, Hinz U, Walczak H, Mechtersheimer G, Koretz K, Herfarth C et al (2002) Expression of TRAIL and TRAIL receptors in colon carcinoma: TRAIL-R1 is an independent prognostic parameter. Clin Cancer Res 8:3734–3740

    PubMed  Google Scholar 

  15. Koornstra JJ, Kleibeuker JH, van Geelen CM, Rijcken FE, Hollema H, de Vries EG et al (2003) Expression of TRAIL (TNF-related apoptosis-inducing ligand) and its receptors in normal colonic mucosa, adenomas, and carcinomas. J Pathol 200:327–335

    Article  CAS  PubMed  Google Scholar 

  16. Satoh K, Kaneko K, Hirota M, Masamune A, Satoh A, Shimosegawa T (2001) Tumour necrosis factor-related apoptosis-inducing ligand and its receptor expression and the pathway of apoptosis in human pancreatic cancer. Pancreas 23:251–258

    Article  CAS  PubMed  Google Scholar 

  17. Ozawa F, Friess H, Kleeff J, Xu ZW, Zimmermann A, Sheikh MS et al (2001) Effects and expression of TRAIL and its apoptosis-promoting receptors in human pancreatic cancer. Cancer Lett 163:71–81

    Article  CAS  PubMed  Google Scholar 

  18. Liao Q, Friess H, Kleeff J, Buchler MW (2001) Differential expression of TRAIL-R3 and TRAIL-R4 in human pancreatic cancer. Anticancer Res 21:3153–3159

    CAS  PubMed  Google Scholar 

  19. Spierings DC, de Vries EG, Timens W, Groen HJ, Boezen HM, de Jong S (2003) Expression of TRAIL and TRAIL death receptors in stage III non-small cell lung cancer tumours. Clin Cancer Res 9:3397–3405

    CAS  PubMed  Google Scholar 

  20. Seitz S, Wassmuth P, Fischer J, Nothnagel A, Jandrig B, Schlag PM et al (2002) Mutation analysis and mRNA expression of trail-receptors in human breast cancer. Int J Cancer 102:117–128

    Article  CAS  PubMed  Google Scholar 

  21. Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19:403–410

    Article  CAS  PubMed  Google Scholar 

  22. Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8:138–140

    CAS  PubMed  Google Scholar 

  23. Westfall PH, Troendle JF (2008) Multiple testing with minimal assumption. Biom J 50:745–755

    Article  PubMed  Google Scholar 

  24. Cretney E, Takeda K, Yagita H, Glaccum M, Peschon JJ, Smyth MJ (2002) Increased susceptibility to tumour initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 168:1356–1361

    CAS  PubMed  Google Scholar 

  25. Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S et al (2001) Involvement of tumour necrosis factor-related apoptosis-inducing ligand in surveillance of tumour metastasis by liver natural killer cells. Nat Med 7:94–100

    Article  CAS  PubMed  Google Scholar 

  26. Luna-More S, Weil B, Bautista D, Garrido E, Florez P, Martinez C (2004) Bcl-2 protein in normal, hyperplastic and neoplastic breast tissues. A metabolite of the putative stem-cell subpopulation of the mammary gland. Histol Histopathol 19:457–463

    CAS  PubMed  Google Scholar 

  27. Chang DW, Xing Z, Pan Y, Algeciras-Schimnich A, Barnhart BC, Yaish-Ohad S et al (2002) c-FLIP(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. EMBO J 21:3704–3714

    Article  CAS  PubMed  Google Scholar 

  28. Chang J, Clark GM, Allred DC, Mohsin S, Chamness G, Elledge RM (2003) Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumour. Cancer 97:545–553

    Article  PubMed  Google Scholar 

  29. Yang Q, Sakurai T, Yoshimura G, Suzuma T, Umemura T, Nakamura M et al (2003) Prognostic value of Bcl-2 in invasive breast cancer receiving chemotherapy and endocrine therapy. Oncol Rep 10:121–125

    CAS  PubMed  Google Scholar 

  30. Daidone MG, Coradini D, Martelli G, Veneroni S (2003) Primary breast cancer in elderly women: biological profile and relation with clinical outcome. Crit Rev Oncol Hematol 45:313–325

    Article  PubMed  Google Scholar 

  31. Ferrero JM, Ramaioli A, Formento JL, Francoual M, Etienne MC, Peyrottes I et al (2000) P53 determination alongside classical prognostic factors in node-negative breast cancer: an evaluation at more than 10-year follow-up. Ann Oncol 11:393–397

    Article  CAS  PubMed  Google Scholar 

  32. Ganten TM, Haas TL, Sykora J, Stahl H, Sprick MR, Fas SC et al (2004) Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs. Cell Death Differ 11(Suppl 1):S86–96

    Article  CAS  PubMed  Google Scholar 

  33. Koschny R, Ganten TM, Sykora J, Haas TL, Sprick MR, Kolb A et al (2007) TRAIL/Bortezomib co-treatment is hepatotoxic but induces cancer-specific apoptosis within a therapeutic window. Hepatology 45(3):649–658

    Article  CAS  PubMed  Google Scholar 

  34. Zolota V, Gerokosta A, Melachrinou M, Kominea A, Aletra C, Scopa CD (1999) Microvessel density, proliferating activity, p53 and bcl-2 expression in in situ ductal carcinoma of the breast. Anticancer Res 19:3269–3274

    CAS  PubMed  Google Scholar 

  35. van Diest PJ, van der Wall E, Baak JP (2004) Prognostic value of proliferation in invasive breast cancer: a review. J Clin Pathol 57:675–681

    Article  PubMed  Google Scholar 

  36. Bhatavdekar JM, Patel DD, Shah NG, Vora HH, Suthar TP, Ghosh N et al (2000) Prolactin as a local growth promoter in patients with breast cancer: GCRI experience. Eur J Surg Oncol 26:540–547

    Article  CAS  PubMed  Google Scholar 

  37. Tsutsui S, Ohno S, Murakami S, Kataoka A, Kinoshita J, Hachitanda Y (2003) Prognostic significance of the coexpression of p53 protein and c-erbB2 in breast cancer. Am J Surg 185:165–167

    Article  CAS  PubMed  Google Scholar 

  38. Climent MA, Segui MA, Peiro G, Molina R, Lerma E, Ojeda B et al (2001) Prognostic value of HER-2/neu and p53 expression in node-positive breast cancer. HER-2/neu effect on adjuvant tamoxifen treatment. Breast 10:67–77

    Article  CAS  PubMed  Google Scholar 

  39. McCarthy MM, Sznol M, DiVito KA, Camp RL, Rimm DL, Kluger HM (2005) Evaluating the expression and prognostic value of TRAIL-R1 and TRAIL-R2 in breast cancer. Clin Cancer Res 11:5188–5194

    Article  CAS  PubMed  Google Scholar 

  40. Natoni A, MacFarlane M, Inoue S, Walewska R, Majid A, Knee D et al (2007) TRAIL signals to apoptosis in chronic lymphocytic leukaemia cells primarily through TRAIL-R1 whereas cross-linked agonistic TRAIL-R2 antibodies facilitate signalling via TRAIL-R2. Br J Haematol 139:568–577

    Article  CAS  PubMed  Google Scholar 

  41. Clancy L, Mruk K, Archer K, Woelfel M, Mongkolsapaya J, Screaton G et al (2005) Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis. Proc Natl Acad Sci U S A 102:18099–18104

    Article  CAS  PubMed  Google Scholar 

  42. Keane MM, Ettenberg SA, Nau MM, Russell EK, Lipkowitz S (1999) Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. Cancer Res 59:734–741

    CAS  PubMed  Google Scholar 

  43. Singh TR, Shankar S, Chen X, Asim M, Srivastava RK (2003) Synergistic interactions of chemotherapeutic drugs and tumour necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand on apoptosis and on regression of breast carcinoma in vivo. Cancer Res 63:5390–5400

    CAS  PubMed  Google Scholar 

  44. Buchsbaum DJ, Zhou T, Grizzle WE, Oliver PG, Hammond CJ, Zhang S et al (2003) Antitumour efficacy of TRA-8 anti-DR5 monoclonal antibody alone or in combination with chemotherapy and/or radiation therapy in a human breast cancer model. Clin Cancer Res 9:3731–3741

    CAS  PubMed  Google Scholar 

  45. Fisher MJ, Virmani AK, Wu L, Aplenc R, Harper JC, Powell SM et al (2001) Nucleotidec substitution in the ectodomain of trail receptor dr4 is associated with lung cancer and head and neck cancer. Clin Cancer Res 7:1688–1697

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Jutta Mohr, Bärbel Moos and Heiko Stahl for excellent technical assistance. Tom M. Ganten and R. Koschny are recipients of a scholarship from the Deutsche Forschungsgemeinschaft (DFG). This project was supported by the Tumorzentrum Heidelberg/Mannheim (T. M. Ganten and H. Walczak) and by a grant from Deutsche Krebshilfe (H. Walczak).

Conflict of interest statement

The authors declare that they have no conflict of interests.

Author information

Authors and Affiliations

  1. Division of Apoptosis Regulation (D040), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Tom M. Ganten, Jaromir Sykora, Ronald Koschny & Henning Walczak

  2. Department of Internal Medicine, University Hospital, Heidelberg, Germany

    Tom M. Ganten, Jaromir Sykora, Ronald Koschny, Emanuela Batke & Wolfgang Stremmel

  3. Department of Pathology, University Hospital, Heidelberg, Germany

    Sebastian Aulmann & Hans-Peter Sinn

  4. Department of Medical Biometry and Epidemiology, University of München, München, Germany

    Ulrich Mansmann

  5. Tumour Immunology Unit, Division of Medicine, Imperial College London, 10th floor, Commonwealth Building, Du Cane Road, London, W12 0NN, UK

    Henning Walczak

Authors
  1. Tom M. Ganten
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaromir Sykora
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ronald Koschny
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emanuela Batke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sebastian Aulmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ulrich Mansmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wolfgang Stremmel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hans-Peter Sinn
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Henning Walczak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Henning Walczak.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ganten, T.M., Sykora, J., Koschny, R. et al. Prognostic significance of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in patients with breast cancer. J Mol Med 87, 995–1007 (2009). https://doi.org/10.1007/s00109-009-0510-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-009-0510-z

Keywords

Search

Navigation