Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Epidermal growth factor receptor activation in prostate cancer by three novel missense mutations

Abstract

While epidermal growth factor receptor (EGFR) dysregulation is known to play a critical role in prostate carcinogenesis, there has been no direct evidence indicating EGFR mutations induce tumorigenesis in prostate cancer. We previously identified four novel EGFR somatic mutations in the EGFR tyrosine kinase domain of prostate cancer patients: G735S, G796S, E804G and R841K. In this study, we investigated the oncogenic potential of these somatic mutations by establishing stable clonal NIH3T3 cells expressing these four mutations and WT EGFR to determine their ability to increase cell proliferation and invasion. In the absence of the EGF ligand, cell proliferation was readily increased in G735S, G796S and E804G mutants compared to WT EGFR. The addition of EGF ligand greatly increased cell growth and transforming ability of these same EGFR mutants. Matrigel invasion assays showed enhanced invasion with G735S, G796S and E804G mutants. Western blot analysis showed that these EGFR mutations enhanced cell growth and invasion via constitutive and hyperactive tyrosine phosphorylation and led to the activation of mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3) and Akt pathways. Our findings demonstrate the oncogenic activation of three novel EGFR somatic missense mutations in prostate cancer. Molecules that regulate the mechanisms of their oncogenic activation represent novel targets for limiting tumor cell progression, and further elucidation of these mutations will have utility in prostate cancer treatment.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Arteaga CL . (2006). EGF receptor mutations in lung cancer: from humans to mice and maybe back to humans. Cancer Cell 9: 421–423.

    Article  CAS  Google Scholar 

  • Barton BE, Karras JG, Murphy TF, Barton A, Huang HF . (2004). Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: direct STAT3 inhibition induces apoptosis in prostate cancer lines. Mol Cancer Ther 3: 11–20.

    Article  CAS  Google Scholar 

  • Bell DW, Lynch TJ, Haserlat SM, Harris PL, Okimoto RA, Brannigan BW et al. (2005). Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol 23: 8081–8092.

    Article  CAS  Google Scholar 

  • Bellezza I, Neuwirt H, Nemes C, Cavarretta IT, Puhr M, Steiner H et al. (2006). Suppressor of cytokine signaling-3 antagonizes cAMP effects on proliferation and apoptosis and is expressed in human prostate cancer. Am J Pathol 169: 2199–2208.

    Article  CAS  Google Scholar 

  • Choi SH, Mendrola JM, Lemmon MA . (2007). EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer. Oncogene 26: 1567–1576.

    Article  CAS  Google Scholar 

  • Chu YW, Runyan RB, Oshima RG, Hendrix MJ . (1993). Expression of complete keratin filaments in mouse L cells augments cell migration and invasion. Proc Natl Acad Sci USA 90: 4261–4265.

    Article  CAS  Google Scholar 

  • Citri A, Yarden Y . (2006). EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7: 505–516.

    Article  CAS  Google Scholar 

  • Danielsen AJ, Maihle NJ . (2002). Ligand-independent oncogenic transformation by the EGF receptor requires kinase domain catalytic activity. Exp Cell Res 275: 9–16.

    Article  CAS  Google Scholar 

  • DeMiguel F, Lee SO, Lou W, Xiao X, Pflug BR, Nelson JB et al. (2002). Stat3 enhances the growth of LNCaP human prostate cancer cells in intact and castrated male nude mice. Prostate 52: 123–129.

    Article  CAS  Google Scholar 

  • Di Fiore PP, Pierce JH, Fleming TP, Hazan R, Ullrich A, King CR et al. (1987). Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells. Cell 51: 1063–1070.

    Article  CAS  Google Scholar 

  • Douglas D, Zhong H, Ro J, Oddoux C, Berger A, Pincus M et al. (2006). Racial difference in somatic mutations of epidermal growth factor receptor in prostate cancer. Front Biosci 11: 2518–2525.

    Article  CAS  Google Scholar 

  • Giri D, Ozen M, Ittmann M . (2001). Interleukin-6 is an autocrine growth factor in human prostate cancer. Am J Pathol 159: 2159–2165.

    Article  CAS  Google Scholar 

  • Greulich H, Chen TH, Feng W, Janne PA, Alvarez JV, Zappaterra M et al. (2005). Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med 2: e313.

    Article  Google Scholar 

  • Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.

    Article  CAS  Google Scholar 

  • Huang HF, Murphy TF, Shu P, Barton AB, Barton BE . (2005). Stable expression of constitutively-activated STAT3 in benign prostatic epithelial cells changes their phenotype to that resembling malignant cells. Mol Cancer 4: 2.

    Article  Google Scholar 

  • Hubbard SR . (2005). EGF receptor inhibition: attacks on multiple fronts. Cancer Cell 7: 287–288.

    Article  CAS  Google Scholar 

  • Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW . (2003). Epidermal growth factor receptor: mechanisms of activation and signaling. Exp Cell Res 284: 31–53.

    Article  CAS  Google Scholar 

  • Lee JC, Vivanco I, Beroukhim R, Huang JH, Feng WL, Debiasi RM et al. (2006). Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med 3: e485.

    Article  Google Scholar 

  • Lee JW, Soung YH, Kim SY, Nam HK, Park WS, Nam SW et al. (2005). Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clin Cancer Res 11: 2879–2882.

    Article  CAS  Google Scholar 

  • Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350: 2129–2139.

    Article  CAS  Google Scholar 

  • Nagahara H, Mimori K, Ohta M, Utsunomiya T, Inoue H, Barnard GF et al. (2005). Somatic mutations of epidermal growth factor receptor in colorectal carcinoma. Clin Cancer Res 11: 1368–1371.

    Article  CAS  Google Scholar 

  • Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S et al. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500.

    Article  CAS  Google Scholar 

  • Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I et al. (2004). EGFR receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 101: 13306–13311.

    Article  CAS  Google Scholar 

  • Ratan HL, Gescher A, Steward WP, Mellon JK . (2003). ErbB receptors: possible therapeutic targets in prostate cancer? BJU Int 92: 890–895.

    Article  CAS  Google Scholar 

  • Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E et al. (1994). A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370: 61–65.

    Article  CAS  Google Scholar 

  • Schreiber AB, Libermann TA, Lax I, Yarden Y, Schlessinger J . (1983). Biological role of epidermal growth factor-receptor clustering. Investigation with monoclonal anti-receptor antibodies. J Biol Chem 258: 846–853.

    CAS  PubMed  Google Scholar 

  • Shao H, Cheng HY, Cook RG, Tweardy DJ . (2003). Identification and characterization of signal transducer and activator of transcription 3 recruitment sites within the epidermal growth factor receptor. Cancer Res 63: 3923–3930.

    CAS  PubMed  Google Scholar 

  • Sherwood ER, Van Dongen JL, Wood CG, Liao S, Kozlowski JM, Lee C . (1998). Epidermal growth factor receptor activation in androgen-independent but not androgen-stimulated growth of human prostatic carcinoma cells. Br J Cancer 77: 855–861.

    Article  CAS  Google Scholar 

  • Sordella R, Bell DW, Haber DA, Settleman J . (2004). Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305: 1163–1167.

    Article  CAS  Google Scholar 

  • Spiotto MT, Chung TD . (2000). STAT3 mediates IL-6-induced growth inhibition in the human prostate cancer cell line LNCaP. Prostate 42: 88–98.

    Article  CAS  Google Scholar 

  • Torring N, Dagnaes-Hansen F, Sorensen BS, Nexo E, Hynes NE . (2003). ErbB1 and prostate cancer: ErbB1 activity is essential for androgen-induced proliferation and protection from the apoptotic effects of LY294002. Prostate 56: 142–149.

    Article  CAS  Google Scholar 

  • Ushiro H, Cohen S . (1980). Identification of phosphotyrosine as a product of epidermal growth factor-activated protein kinase in A-431 cell membranes. J Biol Chem 255: 8363–8365.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J . (2006). An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125: 1137–1149.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Jessie Yu for editorial assistance. This work is supported by an MSKCC SPORE grant to IO, DOD grants to IO and PL.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to I Osman or P Lee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cai, C., Peng, Y., Buckley, M. et al. Epidermal growth factor receptor activation in prostate cancer by three novel missense mutations. Oncogene 27, 3201–3210 (2008). https://doi.org/10.1038/sj.onc.1210983

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210983

Keywords

This article is cited by

Search

Quick links