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:

The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells

Oncogene volume 29, pages 1543–1552 (2010)Cite this article

Abstract

Mutational analysis of oncogenes is critical for our understanding of cancer development. Oncogenome screening has identified a fibroblast growth factor receptor 4 (FGFR4) Y367C mutation in the human breast cancer cell line MDA-MB453. Here, we investigate the consequence of this missense mutation in cancer cells. We show that MDA-MB453 cells harbouring the mutation are insensitive to FGFR4-specific ligand stimulation or inhibition with an antagonistic antibody. Furthermore, the FGFR4 mutant elicits constitutive phosphorylation leading to an activation of the mitogen-activated protein kinase cascade as shown by an enhanced Erk1/2 phosphorylation. Cloning and ectopic expression of the FGFR4 Y367C mutant in HEK293 cells revealed high pErk levels and enhanced cell proliferation. Based on these findings, we propose that FGFR4 may be a driver of tumour growth, particularly when highly expressed or stabilized and constitutively activated through genetic alterations. As such, FGFR4 presents an option for further mutational screening in tumours and is an attractive cancer target with the therapeutic potential.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

  • Ansell A, Farnebo L, Grenman R, Roberg K, Thunell LK . (2009). Polymorphism of FGFR4 in cancer development and sensitivity to cisplatin and radiation in head and neck cancer. Oral Oncol 45: 23–29.

    Article  CAS  Google Scholar 

  • Bange J, Prechtl D, Cheburkin Y, Specht K, Harbeck N, Schmitt M et al. (2002). Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele. Cancer Res 62: 840–847.

    CAS  PubMed  Google Scholar 

  • Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S et al. (2003). Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300: 949.

    Article  CAS  Google Scholar 

  • Bignell G, Smith R, Hunter C, Stephens P, Davies H, Greenman C et al. (2006). Sequence analysis of the protein kinase gene family in human testicular germ-cell tumors of adolescents and adults. Genes Chromosomes Cancer 45: 42–46.

    Article  CAS  Google Scholar 

  • Chesi M, Brents LA, Ely SA, Bais C, Robbiani DF, Mesri EA et al. (2001). Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma. Blood 97: 729–736.

    Article  CAS  Google Scholar 

  • d'Avis PY, Robertson SC, Meyer AN, Bardwell WM, Webster MK, Donoghue DJ . (1998). Constitutive activation of fibroblast growth factor receptor 3 by mutations responsible for the lethal skeletal dysplasia thanatophoric dysplasia type I. Cell Growth Differ 9: 71–78.

    CAS  PubMed  Google Scholar 

  • Dailey L, Ambrosetti D, Mansukhani A, Basilico C . (2005). Mechanisms underlying differential responses to FGF signaling. Cytokine Growth Factor Rev 16: 233–247.

    Article  CAS  Google Scholar 

  • Elbashir SM, Harborth J, Weber K, Tuschl T . (2002). Analysis of gene function in somatic mammalian cells using small interfering RNAs. Methods 26: 199–213.

    Article  CAS  Google Scholar 

  • Ercolino T, Lombardi A, Becherini L, Piscitelli E, Cantini G, Gagliano MS et al. (2008). The Y606C RET mutation causes a receptor gain of function. Clin Endocrinol (Oxf) 69: 253–258.

    Article  CAS  Google Scholar 

  • Eswarakumar VP, Lax I, Schlessinger J . (2005). Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16: 139–149.

    Article  CAS  Google Scholar 

  • Fishman DA, Liu Y, Ellerbroek SM, Stack MS . (2001). Lysophosphatidic acid promotes matrix metalloproteinase (MMP) activation and MMP-dependent invasion in ovarian cancer cells. Cancer Res 61: 3194–3199.

    CAS  PubMed  Google Scholar 

  • Giri D, Ropiquet F, Ittmann M . (1999). Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer. Clin Cancer Res 5: 1063–1071.

    CAS  Google Scholar 

  • Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G et al. (2007). Patterns of somatic mutation in human cancer genomes. Nature 446: 153–158.

    Article  CAS  Google Scholar 

  • Ho HK, Pok S, Streit S, Ruhe JE, Hart S, Lim KS et al. (2009). Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention. J Hepatol 50: 118–127.

    Article  CAS  Google Scholar 

  • Itoh N, Ornitz DM . (2004). Evolution of the Fgf and Fgfr gene families. Trends Genet 20: 563–569.

    Article  CAS  Google Scholar 

  • Koziczak M, Holbro T, Hynes NE . (2004). Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins. Oncogene 23: 3501–3508.

    Article  CAS  Google Scholar 

  • Ma Z, Tsuchiya N, Yuasa T, Inoue T, Kumazawa T, Narita S et al. (2008). Polymorphisms of fibroblast growth factor receptor 4 have association with the development of prostate cancer and benign prostatic hyperplasia and the progression of prostate cancer in a Japanese population. Int J Cancer 123: 2574–2579.

    Article  CAS  Google Scholar 

  • Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D et al. (2004). ONCOMINE: A cancer microarray database and integrated data-mining platform. Neoplasia 6: 1–6.

    Article  CAS  Google Scholar 

  • Roidl A, Berger HJ, Kumar S, Bange J, Knyazev P, Ullrich A . (2009). Resistance to chemotherapy is associated with fibroblast growth factor receptor 4 up-regulation. Clin Cancer Res 15: 2058–2066.

    Article  CAS  Google Scholar 

  • Rousseau F, el Ghouzzi V, Delezoide AL, Legeai-Mallet L, Le MM, Munnich A, Bonaventure J . (1996). Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum Mol Genet 5: 509–512.

    Article  CAS  Google Scholar 

  • Ruhe JE, Streit S, Hart S, Wong CH, Specht K, Knyazev P et al. (2007). Genetic alterations in the tyrosine kinase transcriptome of human cancer cell lines. Cancer Res 67: 11368–11376.

    Article  CAS  Google Scholar 

  • Sasaki H, Okuda K, Kawano O, Yukiue H, Yano M, Fujii Y . (2008). Fibroblast growth factor receptor 4 mutation and polymorphism in Japanese lung cancer. Oncol Rep 20: 1125–1130.

    CAS  PubMed  Google Scholar 

  • Shaoul E, Reich-Slotky R, Berman B, Ron D . (1995). Fibroblast growth factor receptors display both common and distinct signaling pathways. Oncogene 10: 1553–1561.

    CAS  PubMed  Google Scholar 

  • Stephens P, Edkins S, Davies H, Greenman C, Cox C, Hunter C et al. (2005). A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer. Nat Genet 37: 590–592.

    Article  CAS  Google Scholar 

  • Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J et al. (2004). Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431: 525–526.

    Article  CAS  Google Scholar 

  • Streit S, Bange J, Fichtner A, Ihrler S, Issing W, Ullrich A . (2004). Involvement of the FGFR4 Arg388 allele in head and neck squamous cell carcinoma. Int J Cancer 111: 213–217.

    Article  CAS  Google Scholar 

  • Streit S, Mestel DS, Schmidt M, Ullrich A, Berking C . (2006). FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients. Br J Cancer 94: 1879–1886.

    Article  CAS  Google Scholar 

  • Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM et al. (2007). High-throughput oncogene mutation profiling in human cancer. Nat Genet 39: 347–351.

    Article  CAS  Google Scholar 

  • Thussbas C, Nahrig J, Streit S, Bange J, Kriner M, Kates R et al. (2006). FGFR4 Arg388 allele is associated with resistance to adjuvant therapy in primary breast cancer. J Clin Oncol 24: 3747–3755.

    Article  CAS  Google Scholar 

  • Vargas RA, Maegawa GH, Taucher SC, Leite JC, Sanz P, Cifuentes J et al. (2003). Beare-Stevenson syndrome: two South American patients with FGFR2 analysis. Am J Med Genet A 121A: 41–46.

    Article  Google Scholar 

  • Wang J, Yu W, Cai Y, Ren C, Ittmann MM . (2008). Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression. Neoplasia 10: 847–856.

    Article  CAS  Google Scholar 

  • Weinstein IB . (2002). Cancer. Addiction to oncogenes—the Achilles heal of cancer. Science 297: 63–64.

    Article  CAS  Google Scholar 

  • White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S et al. (2005). Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. Am J Hum Genet 76: 361–367.

    Article  CAS  Google Scholar 

  • Wilkie AO . (2005). Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations. Cytokine Growth Factor Rev 16: 187–203.

    Article  CAS  Google Scholar 

  • Yamaguchi F, Saya H, Bruner JM, Morrison RS . (1994). Differential expression of two fibroblast growth factor-receptor genes is associated with malignant progression in human astrocytomas. Proc Natl Acad Sci USA 91: 484–488.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Heike Stubbe for excellent technical support and Dr Peter Czernilofsky for critically reading the manuscript. This work was supported by the National Genome Research Network 2/CancerNet, Grant Number: NGFN2/CancerNet no. 01GS0435, and the Agency for Science Technology and Research (A*STAR), Singapore.

Author information

Author notes

  1. A Roidl

    Present address: 3Current addresses: Pharmaceutical Biology–Biotechnology, Department of Pharmacy, LMU Munich, Germany.,

  2. P Foo

    Present address: 4Current addresses: Sanofi-aventis, Singapore.,

  3. C Mann

    Present address: 5Current addresses: Eurogentec GmbH, Köln, Germany.,

  4. S Bechtold

    Present address: 6Current addresses: Institute for Immunology, Munich, Germany.,

  5. H J Berger

    Present address: 7Current addresses: Celgene GmbH, Munich, Germany.,

  6. S Streit

    Present address: 8Current addresses: Department of Surgery, Technische Universität München, Munich, Germany.,

  7. J E Ruhe

    Present address: 9Current addresses: U3 Pharma, Munich, Germany.,

  8. S Hart

    Present address: 10Current addresses: S*Bio Pte Ltd, Singapore.,

  9. A Roidl and P Foo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany

    A Roidl, C Mann, S Bechtold, H J Berger & A Ullrich

  2. Singapore OncoGenome Programme, Institute of Medical Biology, Singapore

    P Foo, W Wong, S Streit, J E Ruhe, S Hart, A Ullrich & H K Ho

Authors
  1. A Roidl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Foo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Mann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Bechtold
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H J Berger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Streit
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J E Ruhe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Hart
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A Ullrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H K Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H K Ho.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roidl, A., Foo, P., Wong, W. et al. The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells. Oncogene 29, 1543–1552 (2010). https://doi.org/10.1038/onc.2009.432

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2009.432

Keywords

This article is cited by

Search

Advanced search

Quick links