title: K-Ras and β-catenin mutations cooperate with Fgfr3 mutations in mice to promote tumorigenesis in the skin and lung, but not in the bladder.
abstract: The human fibroblast growth factor receptor 3 (FGFR3) gene is frequently mutated in superficial urothelial cell carcinoma (UCC). To test the functional significance of FGFR3 activating mutations as a 'driver' of UCC, we targeted the expression of mutated Fgfr3 to the murine urothelium using Cre-loxP recombination driven by the uroplakin II promoter. The introduction of the Fgfr3 mutations resulted in no obvious effect on tumorigenesis up to 18 months of age. Furthermore, even when the Fgfr3 mutations were introduced together with K-Ras or β-catenin (Ctnnb1) activating mutations, no urothelial dysplasia or UCC was observed. Interestingly, however, owing to a sporadic ectopic Cre recombinase expression in the skin and lung of these mice, Fgfr3 mutation caused papilloma and promoted lung tumorigenesis in cooperation with K-Ras and β-catenin activation, respectively. These results indicate that activation of FGFR3 can cooperate with other mutations to drive tumorigenesis in a context-dependent manner, and support the hypothesis that activation of FGFR3 signaling contributes to human cancer.
authors.affiliation: The Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK.
authors.forename: Imran
authors.initials: I
authors.lastname: Ahmad
authors.forename: Lukram Babloo
authors.initials: LB
authors.lastname: Singh
authors.forename: Mona
authors.initials: M
authors.lastname: Foth
authors.forename: Carol-Ann
authors.initials: CA
authors.lastname: Morris
authors.forename: Makoto Mark
authors.initials: MM
authors.lastname: Taketo
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.forename: Hing Y
authors.initials: HY
authors.lastname: Leung
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Tomoko
authors.initials: T
authors.lastname: Iwata
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases; D018390:Gene Targeting; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D010212:Papilloma / Q000473:pathology; D011230:Precancerous Conditions / Q000473:pathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology; D051176:beta Catenin / Q000235:genetics*
chemical_list: D051176:beta Catenin; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3; D048049:Extracellular Signal-Regulated MAP Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)