FGFR4 GLY388 isotype suppresses motility of MDA-MB-231 breast cancer cells by EDG-2 gene repression.
Clinical investigations of an FGFR4 germline polymorphism, resulting in substitution of glycine by arginine at codon 388 (G388 to R388), have shown a correlation between FGFR4 R388 and aggressive disease progression in cancer patients. Here, we studied the differential effects of the two FGFR4 isotypes on cellular signalling and motility in the MDA-MB-231 human breast cancer cell model. cDNA array analysis showed the ability of FGFR4 G388 to suppress expression of specific genes involved in invasiveness and motility. Further investigations concentrating on cell signalling and motility revealed an abrogation of phosphatidylinositol-3-kinase-dependent LPA-induced Akt activation and cell migration due to downregulation of the LPA receptor Edg-2 in FGFR4 G388-expressing MDA-MB-231 cells. Moreover, FGFR4 G388 expression attenuated the invasivity of the breast cancer cell line and decreased small Rho GTPase activity. We conclude that FGFR4 G388 suppresses cell motility of invasive breast cancer cells by altering signalling pathways and the expression of genes that are required for metastasis. Therefore, the positive effect of FGFR4 R388 on disease progression appears to result from a loss of the tumour suppressor activity displayed by FGFR4 G388 rather than the acquisition or enhancement of oncogenic potential.
Stadler
Christiane Regina
CR
Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18a, D-82152 Martinsried, Germany. stadler@biochem.mpg.de
Knyazev
Pjotr
P
Bange
Johannes
J
Ullrich
Axel
A
D000483:Alleles; D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000503:physiopathology*; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics*; D002478:Cells, Cultured; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D005998:Glycine / Q000235:genetics; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D015398:Signal Transduction
D020033:Protein Isoforms; D049368:Receptors, Lysophosphatidic Acid; D001120:Arginine; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D005998:Glycine