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

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.

• Authors: A Roidl, P Foo, W Wong, C Mann, S Bechtold, H J Berger, S Streit, J E Ruhe, S Hart, A Ullrich, H K Ho
• Journal: Oncogene (Oncogene) Vol. 29 Issue 10 Pg. 1543-52 (Mar 11 2010) ISSN: 1476-5594 [Electronic] England
• PMID: 19946327 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FGF19 protein, human
• Fibroblast Growth Factors
• Receptor, Fibroblast Growth Factor, Type 4
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fibroblast Growth Factors (pharmacology)
• Gene Expression Regulation, Neoplastic
• Genes, Dominant
• Humans
• Immunoblotting
• Mice
• Mutation, Missense
• NIH 3T3 Cells
• Phosphorylation (drug effects)
• RNA Interference
• Receptor, Fibroblast Growth Factor, Type 4 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (genetics)