Abstract
In the growth factor receptor gene FGFR4 the presence of the common single nucleotide polymorphism Arg388 has been associated with progression of various types of cancer including breast cancer. However, a causative relationship is not readily assigned due to genetic heterogeneity in different patient cohorts. To address this issue, we compared the effects of this allele on malignant progression in the WAP-TGFalpha transgenic mouse model of breast cancer. A knock-in strain was generated to introduce an analogous Arg385 allele into the murine FGFR4 gene. Mouse embryonic fibroblasts derived from this strain displayed accelerated cell transformation, with transformed cells exhibiting greater motility and invasive behavior. In the in vivo context of TGFalpha-induced mammary carcinogenesis, tumor development and progression was significantly advanced in tumor mass, size, and onset of pulmonary metastases. Our findings definitively identify the FGFR4 Arg388 allele as a functional prognostic marker for breast cancer progression.
Highlights
In recent years, it has become increasingly clear that in addition to somatic mutations, germ-line alterations such as single nucleotide polymorphisms (SNP) have clinical significance for the development and progression of diseases such as cancer as well as for the definition of a patient's individual response to therapeutic agents [1, 2].In the human FGFR4, a polymorphic nucleotide change in codon 388 converts glycine to arginine in the transmembrane region of the receptor [3]
We further analyzed the effect of the FGFR4Arg385 allele on several processes, including migration, cell proliferation, and cellular life span; FGFR4Arg385-carrying mouse embryonic fibroblasts (MEF) do not show an increased proliferative capacity, life span, or migration compared with FGFR4Gly385 MEFs (Supplementary Fig. S3B and C)
We investigated for the first time the effect of the change of a single nucleotide in the mouse genome in the gene encoding the receptor tyrosine kinase FGFR4 on breast cancer progression in the whey acidic protein (WAP)-transforming growth factor α (TGFα) model
Summary
In the human FGFR4, a polymorphic nucleotide change in codon 388 converts glycine to arginine in the transmembrane region of the receptor [3]. This SNP was shown to be implicated in progression and poor prognosis of various types of human cancer [3,4,5,6,7,8]. Discovered by Bange and colleagues [3], the FGFR4Arg388 allele could be associated with tumor progression in breast and colon cancer patients. A recent study on prostate cancer patients associated the FGFR4Arg388 allele with tumor progression and with initiation [8].
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