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

• Published in: Oncogene Vol. 29; no. 10; pp. 1543 - 1552
• Main Authors: Roidl, A, Foo, P, Wong, W, Mann, C, Bechtold, S, Berger, H J, Streit, S, Ruhe, J E, Hart, S, Ullrich, A, Ho, H K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.03.2010; Nature Publishing Group
• Subjects: Animals; Apoptosis; Biological and medical sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer cells; Cell Biology; Cell Line; Cell Line, Tumor; Cell physiology; Cell Proliferation; Cell receptors; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cells; Ectopic expression; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Fibroblast growth factor receptor 4; Fibroblast growth factor receptors; Fibroblast Growth Factors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; Gene mutations; Genes; Genes, Dominant; Genetic aspects; Gynecology. Andrology. Obstetrics; Human Genetics; Humans; Immunoblotting; Internal Medicine; Kinases; Mammary gland diseases; MAP kinase; Medical sciences; Medicine; Medicine & Public Health; Mice; Missense mutation; Molecular and cellular biology; Mutants; Mutation; Mutation, Missense; NIH 3T3 Cells; Oncogenes; Oncology; original-article; Phosphorylation; Phosphorylation - drug effects; Physiological aspects; Protein kinase; Protein kinase C; Proteins; Receptor, Fibroblast Growth Factor, Type 4 - genetics; Receptor, Fibroblast Growth Factor, Type 4 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; RNA Interference; Signal Transduction - genetics; Tumors; Germany; mutation; cancer; proliferation; FGFR4; oncogenesis; Cell proliferation; Mammary gland diseases; Breast disease; Breast cancer; Mutation; Malignant tumor; Onc gene; Carcinogenesis; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2009.432

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.