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Expression of EGFR, HER2, Phosphorylated ERK and Phosphorylated MEK in Colonic Neoplasms of Familial Adenomatous Polyposis Patients

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Abstract

Purpose

The expression of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) is associated with poor prognosis in sporadic colorectal carcinoma (CRC). EGFR inhibitors are approved for the treatment of refractory CRC. The aim of this study was to investigate the expression of EGFR and HER2 and downstream extracellular signal regulated kinase (ERK) and mitogen activated protein kinase (MAPK) in non-neoplastic colonic mucosa, adenomas and carcinomas from familial adenomatous polyposis coli (FAP) patients, exploring the expression along the adenoma–carcinoma sequence.

Methods

The expression of EGFR, HER2, phosphorylated MAPK/ERK kinase (pMEK) and phosphorylated ERK (pERK) proteins was studied by immunohistochemistry in samples of colonic non-neoplastic mucosa (n = 65), adenomas (n = 149) and adenocarcinomas (n = 16) from each of the 16 FAP patients.

Results

For HER2, only weak cytoplasmic expression was seen in 8% of adenomas, 6% of carcinomas and 3% of the non-neoplastic mucosa. EGFR was expressed in non-neoplastic mucosa, adenomas and carcinomas with a statistically significant increase in expression in adenomas compared with non-neoplastic mucosa (p < 0.001). There was also a statistically significant increase in nuclear staining intensity for pERK (p < 0.001) and pMEK (p < 0.001) in adenomas compared to non-neoplastic mucosa.

Conclusions

This is the first study investigating the expression of these receptors in non-neoplastic mucosa, adenomas and carcinomas from FAP patients. HER2 is not upregulated in the tumours of FAP patients, while EGFR appears to be upregulated in most adenomas and carcinomas, with associated upregulation of pERK and pMEK. We conclude that EGFR and downstream members of its signalling pathway, but not HER2, may be potential therapeutic targets in FAP patients.

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References

  1. Bulow S. The Danish polyposis register. Description of the methods of detection and evaluation of completeness. Dis Colon Rectum. 1984;27(6):351–5.

    Article  PubMed  CAS  Google Scholar 

  2. Bodmer WF et al. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature. 1987;328(6131):614–6.

    Article  PubMed  CAS  Google Scholar 

  3. Fodde R. The APC gene in colorectal cancer. Eur J Cancer. 2002;38(7):867–71.

    Article  PubMed  CAS  Google Scholar 

  4. Debinski HS et al. Colorectal polyp counts and cancer risk in familial adenomatous polyposis. Gastroenterology. 1996;110(4):1028–30.

    Article  PubMed  CAS  Google Scholar 

  5. Kopp R et al. Reduced survival of rectal cancer patients with increased tumor epidermal growth factor receptor levels. Dis Colon Rectum. 2003;46(10):1391–9.

    Article  PubMed  Google Scholar 

  6. Koretz K, Schlag P, Moller P. Expression of epidermal growth factor receptor in normal colorectal mucosa, adenoma, and carcinoma. Virchows Arch A Pathol Anat Histopathol. 1990;416(4):343–9.

    Article  PubMed  CAS  Google Scholar 

  7. Kapitanovic S et al. The expression of p185(HER-2/neu) correlates with the stage of disease and survival in colorectal cancer. Gastroenterology. 1997;112(4):1103–13.

    Article  PubMed  CAS  Google Scholar 

  8. Nathanson DR et al. HER 2/neu expression and gene amplification in colon cancer. Int J Cancer. 2003;105(6):796–802.

    Article  PubMed  CAS  Google Scholar 

  9. Treisman R. Ternary complex factors: growth factor regulated transcriptional activators. Curr Opin Genet Dev. 1994;4(1):96–101.

    Article  PubMed  CAS  Google Scholar 

  10. Chang F, Steelman LS, McCubrey JA. Raf-induced cell cycle progression in human TF-1 hematopoietic cells. Cell Cycle. 2002;1(3):220–6.

    Article  PubMed  CAS  Google Scholar 

  11. Malumbres M et al. Cellular response to oncogenic ras involves induction of the Cdk4 and Cdk6 inhibitor p15(INK4b). Mol Cell Biol. 2000;20(8):2915–25.

    Article  PubMed  CAS  Google Scholar 

  12. Ostrowski J et al. Increased constitutive activity of mitogen-activated protein kinase and renaturable 85 kDa kinase in human-colorectal cancer. Br J Cancer. 1998;78(10):1301–6.

    Article  PubMed  CAS  Google Scholar 

  13. Park KS et al. Differential regulation of MAP kinase cascade in human colorectal tumorigenesis. Br J Cancer. 1999;81(7):1116–21.

    Article  PubMed  CAS  Google Scholar 

  14. Yasui W et al. Expression of epidermal growth factor receptor in human gastric and colonic carcinomas. Cancer Res. 1988;48(1):137–41.

    PubMed  CAS  Google Scholar 

  15. Kruszewski WJ, et al. Expression of HER2 in colorectal cancer does not correlate with prognosis. Dis Markers. 29(5):207-12.

  16. Lee SH et al. Colorectal tumors frequently express phosphorylated mitogen-activated protein kinase. APMIS. 2004;112(4–5):233–8.

    Article  PubMed  CAS  Google Scholar 

  17. Vicent S et al. ERK1/2 is activated in non-small-cell lung cancer and associated with advanced tumours. Br J Cancer. 2004;90(5):1047–52.

    Article  PubMed  CAS  Google Scholar 

  18. Baba Y, et al. Prognostic significance of AMP-activated protein kinase expression and modifying effect of MAPK3/1 in colorectal cancer. Br J Cancer. 2010;103(7):1025-33.

    Article  PubMed  CAS  Google Scholar 

  19. Lee JC et al. Investigation of the prognostic value of coexpressed erbB family members for the survival of colorectal cancer patients after curative surgery. Eur J Cancer. 2002;38(8):1065–71.

    Article  PubMed  CAS  Google Scholar 

  20. Dursun A et al. Expression of Bcl-2 and c-ErbB-2 in colorectal neoplasia. Pathol Oncol Res. 2001;7(1):24–7.

    Article  PubMed  CAS  Google Scholar 

  21. Tsioulias GJ et al. erbB-2 gene expression in colorectal cancer. Jpn J Exp Med. 1990;60(6):343–9.

    PubMed  CAS  Google Scholar 

  22. D'Emilia J et al. Expression of the c-erbB-2 gene product (p185) at different stages of neoplastic progression in the colon. Oncogene. 1989;4(10):1233–9.

    PubMed  Google Scholar 

  23. Herbst RS, Shin DM. Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy. Cancer. 2002;94(5):1593–611.

    Article  PubMed  CAS  Google Scholar 

  24. Yen LC, et al. Activating KRAS mutations and overexpression of epidermal growth factor receptor as independent predictors in metastatic colorectal cancer patients treated with cetuximab. Ann Surg. 2010;251(2):254-60.

    Article  PubMed  Google Scholar 

  25. Hecht JR, et al. Lack of correlation between epidermal growth factor receptor status and response to panitumumab monotherapy in metastatic colorectal cancer. Clin Cancer Res. 2010;16(7):2205-13.

    Article  PubMed  CAS  Google Scholar 

  26. Alferez D et al. Dual inhibition of VEGFR and EGFR signaling reduces the incidence and size of intestinal adenomas in Apc(Min/+) mice. Mol Cancer Ther. 2008;7(3):590–8.

    Article  PubMed  CAS  Google Scholar 

  27. Bashir O et al. Effect of epidermal growth factor administration on intestinal cell proliferation, crypt fission and polyp formation in multiple intestinal neoplasia (Min) mice. Clin Sci (Lond). 2003;105(3):323–30.

    Article  CAS  Google Scholar 

  28. Moran AE et al. Apc deficiency is associated with increased Egfr activity in the intestinal enterocytes and adenomas of C57BL/6J-Min/+ mice. J Biol Chem. 2004;279(41):43261–72.

    Article  PubMed  CAS  Google Scholar 

  29. Schmitz KJ et al. Activation of extracellular regulated kinases (ERK1/2) but not AKT predicts poor prognosis in colorectal carcinoma and is associated with k-ras mutations. Virchows Arch. 2007;450(2):151–9.

    Article  PubMed  CAS  Google Scholar 

  30. Gulmann C et al. Quantitative cell signalling analysis reveals down-regulation of MAPK pathway activation in colorectal cancer. J Pathol. 2009;218(4):514–9.

    Article  PubMed  CAS  Google Scholar 

  31. Attar BM, Atten MJ, Holian O. MAPK activity is down-regulated in human colon adenocarcinoma: correlation with PKC activity. Anticancer Res. 1996;16(1):395–9.

    PubMed  CAS  Google Scholar 

  32. Yuen ST et al. Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res. 2002;62(22):6451–5.

    PubMed  CAS  Google Scholar 

  33. Cunningham D et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337–45.

    Article  PubMed  CAS  Google Scholar 

  34. Karapetis CS et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–65.

    Article  PubMed  CAS  Google Scholar 

  35. Jiang Y et al. Assessment of K-ras mutation: a step toward personalized medicine for patients with colorectal cancer. Cancer. 2009;115(16):3609–17.

    Article  PubMed  CAS  Google Scholar 

  36. Plesec TP, Hunt JL. KRAS mutation testing in colorectal cancer. Adv Anat Pathol. 2009;16(4):196–203.

    Article  PubMed  CAS  Google Scholar 

  37. Torrance CJ et al. Combinatorial chemoprevention of intestinal neoplasia. Nat Med. 2000;6(9):1024–8.

    Article  PubMed  CAS  Google Scholar 

  38. Rice PL et al. Inhibition of extracellular-signal regulated kinases 1/2 is required for apoptosis of human colon cancer cells in vitro by sulindac metabolites. Cancer Res. 2004;64(22):8148–51.

    Article  PubMed  CAS  Google Scholar 

  39. Yeh TC et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 2007;13(5):1576–83.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

The authors are grateful for support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme.

Disclosure/Conflict of Interest Statement

All authors declare that they have no relationships with companies that might have an interest in the submitted work in the previous 3 years; their spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and they have no non-financial interests that may be relevant to the submitted work.

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Authors and Affiliations

  1. Department of Histopathology, Imperial College London, Hammersmith Hospital, DuCane Road, London, W12 0NN, UK

    Jayson Wang & Mona El-Bahrawy

  2. Department of Surgery, Imperial College, Hammersmith Hospital, London, UK

    James Hollingshead

  3. Department of Surgery, Charing Cross Hospital, London, UK

    Nabil El-Masry

  4. Department of Histopathology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK

    Donna Horncastle

  5. St. Mark’s Hospital, London, UK

    Ian Talbot

  6. Wellcome Trust Centre for Human Genetics, University of Oxford and Oxford NIHR Comprehensive Biomedical Research Centre, Oxford, UK

    Ian Tomlinson

  7. Queen Mary University of London, London, UK

    Malcolm R Alison

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  1. Jayson Wang
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  2. James Hollingshead
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  3. Nabil El-Masry
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  4. Donna Horncastle
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  8. Mona El-Bahrawy
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Corresponding author

Correspondence to Mona El-Bahrawy.

Additional information

Jayson Wang and James Hollingshead contributed equally to the work of this manuscript

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Wang, J., Hollingshead, J., El-Masry, N. et al. Expression of EGFR, HER2, Phosphorylated ERK and Phosphorylated MEK in Colonic Neoplasms of Familial Adenomatous Polyposis Patients. J Gastrointest Canc 43, 444–455 (2012). https://doi.org/10.1007/s12029-011-9330-9

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  • DOI: https://doi.org/10.1007/s12029-011-9330-9

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