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On the role of endothelin-converting enzyme-1 (ECE-1) and neprilysin in human breast cancer

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Abstract

Endothelin-1 (ET-1) and its receptors, ETAR and ETBR, are overexpressed in breast carcinomas. However, little is known about the relevance of endothelin-converting enzyme-1 (ECE-1) and ET-1 degrading neprilysin (NEP). In this study, expression of ECE-1 and NEP was determined in 600 breast cancer tissue samples by immunohistochemistry; staining results were correlated with clinicopathological parameters. For ECE-1 expression, we found a significant correlation with VEGF (P < 0.001) and ETAR expression (P = 0.048). While patients with ECE-1 overexpressing tumours had more frequent disease recurrence (P = 0.03), NEP overexpression correlated with improved disease-free survival (DFS) (P = 0.023) and less frequent metastasis (P = 0.046). Also, a decrease of NEP expression with malignant progression (G1–G3) was found. ECE-1 inhibition using the selective ECE-1 inhibitor RO 67-7447 in MCF-7 breast cancer cells led to a significantly decreased ET-1 expression and reduced cell invasiveness (54.3% of controls, P = 0.014). Our results indicate that overexpression of ECE-1 is associated with unfavourable outcome, whereas NEP positively influences survival. Thus, expression of ECE-1 and NEP may have prognostic relevance. Due to the anti-invasive effect of the selective ECE-1 inhibitor, targeting ECE-1 may represent an innovative option in future breast cancer therapy.

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References

  1. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T (1988) A novel potent vasoconstrictor peptide produced by vasuclar endothelial cells. Nature 322:411–415

    Article  Google Scholar 

  2. Levin ER (1995) Endothelins. N Engl J Med 333:356–363

    Article  PubMed  CAS  Google Scholar 

  3. Nelson J, Bagnato A, Battistini B, Nisen P (2003) The endothelin axis: emerging role in cancer. Nat Rev Cancer 3:110–116

    Article  PubMed  CAS  Google Scholar 

  4. Bagnato A, Salani D, Di Castro V, Wu-Wong JR, Tecce R, Nicotra MR, Venuti A, Natali PG (1999) Expression of endothelin-1 and endothelin A receptor in ovarian carcinoma: evidence for an autocrine role in tumor growth. Cancer Res 59:1–8

    Google Scholar 

  5. Asham E, Shankar A, Loizidou M, Fredericks S, Miller K, Boulos PB, Burnstock G, Taylor I (2001) Increased endothelin-1 in colorectal cancer and reduction of tumor growth by ET(A)receptor antagonism. Br J Cancer 30:1759–1763

    Article  CAS  Google Scholar 

  6. Bagnato A, Tecce R, Di Castro V, Catt KJ (1997) Activation of mitogenic signaling by endothelin-1 in ovarian carcinoma cells. Cancer Res 57:1306–1311

    PubMed  CAS  Google Scholar 

  7. Rosano L, Varmi M, Salani D, Di Castro V, Spinella F, Natali PG, Bagnato A (2001) Endothelin-1 induces tumor proteinase activation and invasiveness of ovarian carcinoma cells. Cancer Res 61:8340–8346

    PubMed  CAS  Google Scholar 

  8. Spinella F, Rosano L, Di Castro V, Natali PG, Bagnato A (2002) Endothelin-1 induces vascular endothelial growth factor by increasing hypoxia-inducible factor 1α in ovarian cancer cells. J Biol Chem 277:27850–27855

    Article  PubMed  CAS  Google Scholar 

  9. Salani D, Di Castro V, Nicotra MR, Rosano L, Tecce R, Venuti A, Natali PG, Bagnato A (2000) Role of endothelin-1 in neovascularization of ovarian carcinoma. Am J Pathol 157:1537–1547

    PubMed  CAS  Google Scholar 

  10. Del Bufalo D, Di Castro V, Biroccio A, Varmi M, Salani D, Rosano L, Trisciuoglio D, Spinella F, Bagnato A (2002) Endothelin-1 protects ovarian carcinoma cells against paclitaxel-induced apoptosis: requirement for Akt activation. Mol Pharmacol 61:524–532

    Article  PubMed  Google Scholar 

  11. Rosano L, Di Castro V, Spinella F, Decandia S, Natali PG, Bagnato A (2006) ZD4054, a potent endothelin receptor A antagonist, inhibits ovarian carcinoma cell proliferation. Exp Biol Med (Maywood) 231:1132–1135

    CAS  Google Scholar 

  12. Wülfing P, Diallo R, Kersting C, Wülfing C, Poremba C, Rody A, Greb RR, Böcker W, Kiesel L (2003a) Expression of endothelin-1, endothelin-A and endothelin-B receptor in human breast cancer and correlation with long-term follow-up. Clin Cancer Res 9:4125–4131

    Google Scholar 

  13. Wülfing P, Kersting C, Tio J, Fischer RJ, Wülfing C, Poremba C, Diallo R, Böcker W, Kiesel L (2004) Endothelin-1-, endothelin-A-, and endothelin-B-receptor expression is correlated with vascular endothelial growth factor expression and angiogenesis in breast cancer. Clin Cancer Res 10:2393–2400

    Article  PubMed  Google Scholar 

  14. Bagnato A, Cirilli A, Salani D, Simeone P, Muller A, Nicotra MR, Natali PG, Venuti A (2002) Growth inhibition of cervix carcinoma cells in vivo by endothelin A receptor blockade. Cancer Res 62:6381–6384

    PubMed  CAS  Google Scholar 

  15. Pirtskhalaishvili G, Nelson JB (2002) The endothelin receptor: a novel target for anticancer therapy. Am J Cancer 1:1–7

    Google Scholar 

  16. Xu D, Emoto N, Giaid A, Slaughter C, Kaw S, de Wit D, Yanagisawa M (1994) ECE-1: a membrane-bound metalloprotease that catalyzes the proteolytic activation of endothelin-1. Cell 78:473–485

    Article  PubMed  CAS  Google Scholar 

  17. Yanagisawa H, Yanagisawa M, Kapur RP, Richardson JA, Williams SC, Clouthier DE, de Wit D, Emoto N, Hammer RE (1998) Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development 125:825–836

    PubMed  CAS  Google Scholar 

  18. Turner AJ, Brown CD, Carson JA, Barnes K (2000) The neprilysin family in health and disease. Adv Exp Med Biol 477:229–240

    Article  PubMed  CAS  Google Scholar 

  19. Shipp MA, Tarr GE, Chen CY, Switzer SN, Hersh LB, Stein H, Sunday ME, Reinherz EL (1991) CD10/neutral endopeptidase-24.11 hydrolyzes bombesin-like peptides and regulates the growth of small-cell carcinomas of the lung. Proc Natl Acad Sci USA 88:10662–10666

    Article  PubMed  CAS  Google Scholar 

  20. Papandreou CN, Usmani BA, Geng Y, Bogenrieder T, Freeman R, Wilk S, Finstad CL, Reuter VE, Powell CT, Scheinberg D, Magill C, Scher HI, Albino AP, Nanus DM (1998) Neutral endopeptidase 24.11 loss in metastatic human prostate cancer contributes to androgen-independent progression. Nat Med 4:50–57

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  22. Wülfing P, Diallo R, Müller C, Wülfing C, Poremba C, Heinecke A, Rody A, Greb RR, Böcker W, Kiesel L (2003b) Analysis of cyclooxygenase-2 expression in human breast cancer: high throughput tissue microarray analysis. J Cancer Res Clin Oncol 129:375–382

    Article  CAS  Google Scholar 

  23. Wülfing P, Götte M, Sonntag B, Kersting C, Schmidt H, Wülfing C, Bürger H, Greb R, Bocker W, Kiesel L (2005) Overexpression of endothelin-A-receptor in breast cancer: regulation by estradiol and cobalt-chloride induced hypoxia. Int J Oncol 26:951–960

    PubMed  Google Scholar 

  24. Berger Y, Dehmlow H, Blum-Kaelin D, Kitas EA, Loffler BM, Aebi JD, Juillerat-Jeanneret L (2005) Endothelin-converting enzyme-1 inhibition and growth of human glioblastoma cells. J Med Chem 48:483–498

    Article  PubMed  CAS  Google Scholar 

  25. Lim D, Phan TT, Yip GW, Bay BH (2006) Up-regulation of metallothionein isoforms in keloid keratinocytes. Int J Mol Med 17:385–389

    PubMed  CAS  Google Scholar 

  26. Sumitomo M, Shen R, Nanus DM (2005) Involvement of neutral endopeptidase in neoplastic progression. Biochim Biophys Acta 1751:52–59

    PubMed  CAS  Google Scholar 

  27. Gasparini G (2001) Clinical significance of determination of surrogate markers of angiogenesis in breast cancer. Crit Rev Oncol Hematol 37:97–114

    Article  PubMed  CAS  Google Scholar 

  28. Song J, Aumüller G, Xiao F, Wilhelm B, Albrecht M (2004) Cell specific expression of CD10/neutral endopeptidase 24.11 gene in human prostatic tissue and cells. Prostate 58:394–405

    Article  PubMed  CAS  Google Scholar 

  29. Terauchi M, Kajiyama H, Shibata K, Ino K, Mizutani S, Kikkawa F (2005) Anti-progressive effect of neutral endopeptidase 24.11 (NEP/CD10) on cervical carcinoma in vitro and in vivo. Oncology 69:52–62

    Article  PubMed  CAS  Google Scholar 

  30. Kajiyama H, Shibata K, Terauchi M, Morita T, Ino K, Mizutani S, Kikkawa F (2005) Neutral endopeptidase 24.11/CD10 suppresses progressive pptential in ovarian carcinoma in vitro and in vivo. Clin Cancer Res 11:1798–1808

    Article  PubMed  CAS  Google Scholar 

  31. Usmani BA, Harden B, Maitland NJ, Turner AJ (2002) Differential expression of neutral endopeptidase-24.11 (neprilysin) and endothelin-converting enzyme in human prostate cancer cell lines. Clin Sci (Lond) 103:314S-317S

    CAS  Google Scholar 

  32. Awano S, Dawson LA, Hunter AR, Turner AJ, Usami BA (2006) Endothelin system in oral squamous carcinoma cells: specific siRNA targeting of ECE-1 blocks cell proliferation. Int J Cancer 118:1645–1652

    Article  PubMed  CAS  Google Scholar 

  33. Saijonmaa O, Nyman T, Fyhrquist F (1992) Endothelin-1 stimulates its own synthesis in human endothelial cells. Biochem Biophys Res Commun 188:286–291

    Article  PubMed  CAS  Google Scholar 

  34. Carroll VA, Ashcroft M (2006) Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Cancer Res 66:6262–6270

    Article  Google Scholar 

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Acknowledgements

We thank Barbara Kloke and Birgit Pers for excellent technical assistance. Funding was provided by Münster University Hospital “Innovative Medizinische Forschung” IMF grants WÜ 120332 and WÜ 110527. Work in G.W.Y.’s lab is supported by Grants NMRC/0772/2003 and NMRC/1023/2005 from the National Medical Research Council, Singapore.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University Hospital of Münster, Albert-Schweitzer-Str. 33, 48149, Münster, Germany

    Martin Smollich, Martin Götte, Jeanett Fischgräbe, Isabel Radke, Ludwig Kiesel & Pia Wülfing

  2. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore

    George W. Yip & Eng-Siang Yong

  3. Gerhard-Domagk-Institute of Pathology, University of Münster, 48149, Munster, Germany

    Christian Kersting

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  1. Martin Smollich
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  2. Martin Götte
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Correspondence to Pia Wülfing.

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Smollich, M., Götte, M., Yip, G.W. et al. On the role of endothelin-converting enzyme-1 (ECE-1) and neprilysin in human breast cancer. Breast Cancer Res Treat 106, 361–369 (2007). https://doi.org/10.1007/s10549-007-9516-9

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  • DOI: https://doi.org/10.1007/s10549-007-9516-9

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