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Inverse prognostic impact of ErbB2 mRNA and protein expression level in tumors of soft tissue sarcoma patients

Inverse Korrelation von ErbB2-mRNA und der Proteinexpression in Weichteilsarkompatienten

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Abstract

Background

Human epidermal growth factor receptor 2 (ErbB2) is overexpressed in a variety of human malignancies. Moreover, ErbB2 has been reported to influence cancer patient survival and progression of different tumor entities. However, information regarding the prognostic impact of ErbB2 in soft tissue sarcoma (STS) patients is limited and conflicting.

Material and methods

ErbB2 mRNA and protein levels were defined by quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA), and the prognostic impact of ErbB2 mRNA and protein levels in tumor tissue of 124 soft tissue sarcoma patients were investigated.

Results

The median ErbB2 mRNA expression level in tumor tissue was decreased 3.9-fold compared to non-neoplastic surrounding tissue (p = 0.001). Furthermore, an increased ErbB2 mRNA expression level was associated with an improved tumor-specific survival (p = 0.01, log rank test). Multivariate Cox’s proportional hazard regression analyses revealed an increased ErbB2 mRNA expression level as an independent favorable prognostic factor for tumor-specific survival of STS patients (n = 124; RR = 3.0; 95 % CI = 1.6–5.7; p < 0.001). In addition, multivariate Cox’s proportional hazard regression analyses showed that an increased ErbB2 protein expression level correlated with poorer recurrence-free survival of STS patients (n = 47; RR = 9.9; 95 % CI = 1.7–59.7; p = 0.012), in particular for STS patients who received postoperative radiotherapy (n = 27; RR = 17.9; 95 % CI = 1.3–247.7; p = 0.031).

Conclusion

This study suggests an inverse prognostic value of ErbB2 mRNA and protein expression level.

Zusammenfassung

Hintergrund

Der epidermale Wachstumsfaktorrezeptor (ErbB2) wird in einer Vielzahl von humanen Malignitäten überexprimiert. Darüber hinaus beeinflusst ErbB2 das Überleben von Tumorpatienten und die Progression verschiedener Tumorentitäten. Allerdings stehen nur begrenzte und widersprüchliche Daten zur prognostischen Bedeutung des ErbB2 in Weichteilsarkompatienten zur Verfügung.

Material und Methoden

Der ErbB2-mRNA- und Proteingehalt von 124 Weichteilsarkomen wurde mittels quantitativer Real-Time-PCR und „Enzyme Linked Immunosorbent Assay“ (ELISA) bestimmt und deren Einfluss auf das Überleben der Weichteilsarkompatienten untersucht.

Ergebnisse

Der mediane ErbB2-mRNA-Gehalt im Tumorgewebe war im Vergleich zum angrenzenden Normalgewebe 3,9-fach geringer (p = 0,001). Darüber hinaus war ein erhöhter ErbB2-mRNA-Gehalt mit einem besseren tumorspezifischen Überleben assoziiert (p = 0,01; Log-rank-Test). In multivariaten Cox-Regressionsanalysen erwies sich der ErbB2-mRNA-Gehalt als unabhängiger prognostischer Marker für das Überleben von Weichteilsarkompatienten (n = 124; RR = 3,0; 95 %-KI  1,6–5,7; p < 0,001). Multivariate Cox-Regressionsanalysen zeigen darüber hinaus, dass ein erhöhter ErbB2-Proteingehalt mit einem schlechten rezidivfreien Überleben von Weichteilsarkompatienten (n = 47; RR = 9,9; 95 %-KI 1,7–59,7; p = 0,012) und insbesondere mit einem schlechteren rezidivfreien Überleben von Weichteilsarkompatienten nach postoperativer Radiotherapie korreliert ist (n = 27; RR = 17,9; 95 %-KI 1,3–247,7; p = 0,031).

Schlussfolgerung

Diese Studie legt eine inverse prognostische Bedeutung des mRNA- und Proteingehalts von ErbB2 für Patienten mit Weichteilsarkomen nahe.

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References

  1. Greve B, Sheikh-Mounessi F, Kemper B et al (2012) Survivin, a target to modulate the radiosensitivity of Ewing’s sarcoma. Strahlenther Onkol 188:1038–1047

    Article  PubMed  CAS  Google Scholar 

  2. Eckert F, Gani C, Kluba T et al (2013) Effect of concurrent chemotherapy and hyperthermia on outcome of preoperative radiotherapy of high-risk soft tissue sarcomas. Strahlenther Onkol 189:482–485

    Article  PubMed  CAS  Google Scholar 

  3. Enzinger FM, Weiss SW (1995) Soft tissue tumours. Mosby, St. Louis

    Google Scholar 

  4. Guillou L, Coindre JM, Bonichon F et al (1997) Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol 15:350–362

    PubMed  CAS  Google Scholar 

  5. Moasser MM (2007) The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 26:6469–6487

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Kasprzyk PG, Song SU, Difiore PP et al (1992) Therapy of an animal-model of human gastric-cancer using a combination of anti-ErbB-2 monoclonal-antibodies. Cancer Res 52: 2771–2776

    PubMed  CAS  Google Scholar 

  7. Sauer G, Deissler H, Kurzeder C et al (2002) New molecular targets of breast cancer therapy. Strahlenther Onkol 178:123–133

    Article  PubMed  Google Scholar 

  8. Olayioye MA (2001) Update on HER-2 as a target for cancer therapy—intracellular signaling pathways of ErbB2/HER-2 and family members. Breast Cancer Res 3:385–389

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Guo GZ, Wang TL, Gao Q et al (2004) Expression of ErbB2 enhances radiation-induced NF-kappa B activation. Oncogene 23:535–545

    Article  PubMed  CAS  Google Scholar 

  10. Fehm T, Maul H, Gebauer S et al (2005) Prediction of axillary lymph node status of breast cancer patients by tumorbiological factors of the primary tumor. Strahlenther Onkol 181:580–586

    Article  PubMed  Google Scholar 

  11. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127–137

    Article  PubMed  CAS  Google Scholar 

  12. Karunagaran D, Tzahar E, Beerli RR et al (1996) ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J 15:254–264

    PubMed  CAS  PubMed Central  Google Scholar 

  13. Tzahar E, Waterman H, Chen XM et al (1996) A hierarchical network of interreceptor interactions determines signal transduction by neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 16:5276–5287

    PubMed  CAS  PubMed Central  Google Scholar 

  14. GrausPorta D, Beerli RR, Daly JM et al (1997) ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 16:1647–1655

    Article  CAS  Google Scholar 

  15. Murphy CG, Morris PG (2012) Recent advances in novel targeted therapies for HER2-positive breast cancer. Anticancer Drugs 23:765–776

    Article  PubMed  CAS  Google Scholar 

  16. Foster H, Knox S, Ganti AK et al (2003) HER-2/neu overexpression detected by immunohistochemistry in soft tissue sarcomas. Am J Clin Oncol-Canc 26:188–191

    Article  CAS  Google Scholar 

  17. Sato T, Peiper M, Heinecke A et al (2003) Expression of HER2/neu does not correlate with survival in soft tissue sarcoma. Onkologie 26:268–271

    Article  PubMed  CAS  Google Scholar 

  18. Potti A, Ganti AK, Foster H et al (2004) Immunohistochemical detection of HER-2/neu, c-kit (CD117) and vascular endothelial growth factor (VEGF) overexpression in soft tissue sarcomas. Anticancer Res 24:333–337

    PubMed  CAS  Google Scholar 

  19. Nuciforo PG, Pellegrini C, Fasani R et al (2003) Molecular and immunohistochemical analysis of HER2/neu oncogene in synovial sarcoma. Hum Pathol 34:639–645

    Article  PubMed  CAS  Google Scholar 

  20. Wurl P, Kappler M, Meye A et al (2002) Co-expression of survivin and TERT and risk of tumour-related death in patients with soft tissue sarcoma. Lancet 359:943–945

    Google Scholar 

  21. Taubert H, Greither T, Kaushal D et al (2007) Expression of the stem cell self-renewal gene Hiwi and risk of tumour-related death in patients with soft tissue sarcoma. Oncogene 26:1098–1100

    Google Scholar 

  22. Hahnel A, Wichmann H, Kappler M et al (2010) Effects of osteopontin inhibition on radiosensitivity of MDA-MB-231 breast cancer cells. Radiation Oncology 5:82

    Google Scholar 

  23. Muller V, Thomssen C, Karakas C et al (2003) Quantitative assessment of HER-2/neu protein concentration in breast cancer by enzyme-linked immunosorbent assay. Int J Biol Markers 18:13–20

    PubMed  CAS  Google Scholar 

  24. Hernan R, Fasheh R, Calabrese C et al (2003) ERBB2 up-regulates S100A4 and several other prometastatic genes in medulloblastoma. Cancer Res 63:140–148

    PubMed  CAS  Google Scholar 

  25. Verbeek BS, Adriaansen-Slot SS, Vroom TM et al (1998) Overexpression of EGFR and c-erbB2 causes enhanced cell migration in human breast cancer cells and NIH3T3 fibroblasts. FEBS Lett 425:145–150

    Article  PubMed  CAS  Google Scholar 

  26. Zafrakas M, Zepiridis L, Theodoridis TD et al (2009) ErbB2 (HER2) protein expression in uterine sarcomas. Eur J Gynaecol Oncol 30:292–294

    PubMed  CAS  Google Scholar 

  27. Amant F, Vloeberghs V, Woestenborghs H et al (2004) ErbB-2 gene overexpression and amplification in uterine sarcomas. Gynecol Oncol 95:583–587

    Article  PubMed  CAS  Google Scholar 

  28. George E, Niehans GA, Swanson PE et al (1992) Overexpression of the C-ErbB-2 oncogene in sarcomas and small round-cell tumors of childhood—an immunohistochemical investigation. Arch Pathol Lab Med 116:1033–1035

    PubMed  CAS  Google Scholar 

  29. Thomas DG, Giordano TJ, Sanders D et al (2005) Expression of receptor tyrosine kinases epidermal growth factor receptor and HER-2/neu in synovial sarcoma. Cancer 103:830–838

    Article  PubMed  CAS  Google Scholar 

  30. Andrade CR, Takahama JA, Nishimoto IN et al (2010) Rhabdomyosarcoma of the head and neck: a clinicopathological and immunohistochemical analysis of 29 cases. Braz Dent J 21:68–73

    Article  PubMed  Google Scholar 

  31. Krskova L, Kalinova M, Brizova H et al (2007) Molecular and immunohistochemical analysis of ERBB2 expression in correlation with proliferation rate. in synovial sarcoma. Diagn Mol Pathol 16:211–217

    Article  PubMed  CAS  Google Scholar 

  32. Akatsuka T, Wada T, Kokai Y et al (2002) ErbB2 expression is correlated with increased survival of patients with osteosarcoma. Cancer 94:1397–1404

    Article  PubMed  CAS  Google Scholar 

  33. Ljuslinder I, Malmer B, Golovleva I et al (2005) Increased copy number at 3p14 in breast cancer. Breast Cancer Res 7:R719–R727

    Google Scholar 

  34. Underwood M, Bartlett J, Reeves J et al (1995) C-Erbb-2 gene amplification—a molecular marker in recurrent bladder-tumors. Cancer Res 55:2422–2430

    PubMed  CAS  Google Scholar 

  35. Haugen DRF, Akslen LA, Varhaug JE et al (1992) Expression of C-Erbb-2 protein in papillary thyroid carcinomas. Br J Cancer 65:832–837

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Gonzalez-Angulo AM, Litton JK, Broglio KR et al (2009) High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol 27:5700–5706

    Article  PubMed  PubMed Central  Google Scholar 

  37. Cao N, Li SY, Wang ZQ et al (2009) NF-kappa B-mediated HER2 overexpression in radiation-adaptive resistance. Radiat Res 171:9–21

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Akatsuka T, Wada T, Kokai Y et al (2001) Loss of ErbB2 expression in pulmonary metastatic lesions in osteosarcoma. Oncology 60:361–366

    Article  PubMed  CAS  Google Scholar 

  39. Dawood S, Broglio K, Esteva FJ et al (2008) Defining prognosis for women with breast cancer and CNS metastases by HER2 status. Ann Oncol 19:1242–1248

    Article  PubMed  CAS  Google Scholar 

  40. Mittra I, Redkar AA, Badwe RA (1995) Prognosis of breast-cancer—evidence for interaction between C-ErbB-2 overexpression and number of involved axillary lymph-nodes. J Surg Oncol 60:106–111

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank our colleagues from the Department of Radiotherapy and Department of Oral and Maxillofacial Plastic Surgery for contributing to this study and for their continuous support. We also thank Gabriele Thomas and Kathrin Spröte for their excellent technical assistance. ELISA Kits to quantify ErbB2 protein levels were kindly supported by Wilex Inc., Cambridge, MA, USA.

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Authors and Affiliations

  1. Department of Radiotherapy, Martin-Luther-University of Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle (Saale), Germany

    Henri Wichmann, Antje Güttler,  Matthias Bache &  Dirk Vordermark

  2. Department of Oral and Maxillofacial Plastic Surgery, Martin-Luther-University of Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle (Saale), Germany

    Henri Wichmann,  Alexander W. Eckert &  Matthias Kappler

  3. Clinic of Urology, FA University Hospital Erlangen, Hartmannstr. 14, 91054, Erlangen, Germany

    Helge Taubert

  4. Department of Gynaecology, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle (Saale), Germany

    Martina Vetter

  5. Department of General and Visceral Surgery, Diakoniekrankenhaus, Advokatenweg 1, 06114, Halle (Saale), Germany

    Peter Würl

  6. Department of Pathology, Martin-Luther-University Halle-Wittenberg, Große Steinstraße 52, 06108, Halle (Saale), Germany

    Hans J. Holzhausen

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  1. Henri Wichmann
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Correspondence to Henri Wichmann.

Additional information

Matthias Kappler and Dirk Vordermark contributed equally to this article.

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Wichmann, H., Güttler, A., Bache, M. et al. Inverse prognostic impact of ErbB2 mRNA and protein expression level in tumors of soft tissue sarcoma patients. Strahlenther Onkol 190, 912–918 (2014). https://doi.org/10.1007/s00066-014-0655-8

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  • DOI: https://doi.org/10.1007/s00066-014-0655-8

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