Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression.
Fibroblast growth factor receptor 4 (FGFR-4) is expressed at significant levels in almost all human prostate cancers, and expression of its ligands is ubiquitous. A common polymorphism of FGFR-4 in which arginine (Arg(388)) replaces glycine (Gly(388)) at amino acid 388 is associated with progression in human prostate cancer. We show that the FGFR-4 Arg(388) polymorphism, which is present in most prostate cancer patients, results in increased receptor stability and sustained receptor activation. In patients bearing the FGFR-4 Gly(388) variant, expression of Huntingtin-interacting protein 1 (HIP1), which occurs in more than half of human prostate cancers, also results in FGFR-4 stabilization. This is associated with enhanced proliferation and anchorage-independent growth in vitro. Our findings indicate that increased receptor stability and sustained FGFR-4 signaling occur in most human prostate cancers due to either the presence of a common genetic polymorphism or the expression of a protein that stabilizes FGFR-4. Both of these alterations are associated with clinical progression in patients with prostate cancer. Thus, FGFR-4 signaling and receptor turnover are important potential therapeutic targets in prostate cancer.
Wang
Jianghua
J
Department of Pathology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX 77030, USA.
Yu
Wendong
W
Cai
Yi
Y
Ren
Chengxi
C
Ittmann
Michael M
MM
D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D014644:Genetic Variation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008024:Ligands; D008297:Male; D010766:Phosphorylation; D011110:Polymorphism, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; C073368:HIP1 protein, human; D008024:Ligands; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4