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

Ahmad, I. , Singh, L.B., Foth, M., Morris, C.-A., Taketo, M.M., Wu, X.-R., Leung, H.Y. , Sansom, O.J. and Iwata, T. (2011) 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 and Mechanisms, 4(4), pp. 548-555. (doi:10.1242/dmm.006874)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ahmad, Dr Imran and Leung, Professor Hing and Iwata, Dr Tomoko and Singh, Mr Lukram and Sansom, Professor Owen
Authors: Ahmad, I., Singh, L.B., Foth, M., Morris, C.-A., Taketo, M.M., Wu, X.-R., Leung, H.Y., Sansom, O.J., and Iwata, T.
Subjects:R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Disease Models and Mechanisms
Publisher:The Company of Biologists Ltd.
ISSN:1754-8403
Published Online:18 April 2011
Copyright Holders:Copyright © 2011 The Company of Biologists Ltd.
First Published:First published in Disease Models & Mechanisms 4(4):548-555
Publisher Policy:Reproduced under a Creative Commons Licence

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