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

SUMMARY 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...

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Main Authors:	Imran Ahmad, Lukram Babloo Singh, Mona Foth, Carol-Ann Morris, Makoto Mark Taketo, Xue-Ru Wu, Hing Y. Leung, Owen J. Sansom, Tomoko Iwata
Format:	Article
Language:	English
Published:	The Company of Biologists 2011-07-01
Series:	Disease Models & Mechanisms
Online Access:	http://dmm.biologists.org/content/4/4/548

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spelling	doaj-4cb9c5d92474456da4eabdd48f5bb9052020-11-25T00:11:42ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112011-07-014454855510.1242/dmm.006874006874K-Ras and β-catenin mutations cooperate with Fgfr3 mutations in mice to promote tumorigenesis in the skin and lung, but not in the bladderImran AhmadLukram Babloo SinghMona FothCarol-Ann MorrisMakoto Mark TaketoXue-Ru WuHing Y. LeungOwen J. SansomTomoko IwataSUMMARY 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.http://dmm.biologists.org/content/4/4/548
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Imran Ahmad Lukram Babloo Singh Mona Foth Carol-Ann Morris Makoto Mark Taketo Xue-Ru Wu Hing Y. Leung Owen J. Sansom Tomoko Iwata
spellingShingle	Imran Ahmad Lukram Babloo Singh Mona Foth Carol-Ann Morris Makoto Mark Taketo Xue-Ru Wu Hing Y. Leung Owen J. Sansom Tomoko Iwata 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 Disease Models & Mechanisms
author_facet	Imran Ahmad Lukram Babloo Singh Mona Foth Carol-Ann Morris Makoto Mark Taketo Xue-Ru Wu Hing Y. Leung Owen J. Sansom Tomoko Iwata
author_sort	Imran Ahmad
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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	The Company of Biologists
series	Disease Models & Mechanisms
issn	1754-8403 1754-8411
publishDate	2011-07-01
description	SUMMARY 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.
url	http://dmm.biologists.org/content/4/4/548
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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

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