Abstract
Mice of the C57BL/6 strain are resistant to the development of skin squamous carcinomas (SCCs) induced by an activated Ras oncogene, whereas FVB/N mice are highly susceptible1. The genetic basis of this difference in phenotype is unknown. Here we show that susceptibility to SCC is under the control of a carboxy-terminal polymorphism in the mouse Ptch gene. F1 hybrids between C57BL/6 and FVB/N strains ((B6FVB)F1) are resistant to Ras-induced SCCs, but resistance can be overcome either by elimination of the C57BL/6 Ptch allele (PtchB6) or by overexpression of the FVB/N Ptch allele (PtchFVB) in the epidermis of K5Hras-transgenic (B6FVB)F1 hybrid mice. The human Patched (PTCH) gene is a classical tumour suppressor gene for basal cell carcinomas and medulloblastomas, the loss of which causes increased signalling through the Sonic Hedgehog (SHH) pathway2,3,4,5. SCCs that develop in PtchB6+/- mice do not lose the wild-type Ptch gene or show evidence of increased SHH signalling. Although PtchFVB overexpression can promote SCC formation, continued expression is not required for tumour maintenance, suggesting a role at an early stage of tumour cell lineage commitment. The Ptch polymorphism affects Hras-induced apoptosis, and binding to Tid1, the mouse homologue of the Drosophila l(2)tid tumour suppressor gene. We propose that Ptch occupies a critical niche in determining basal or squamous cell lineage, and that both tumour types can arise from the same target cell depending on carcinogen exposure and host genetic background.
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Acknowledgements
We thank T. Curran for providing Ptch+/- mice, E. Bailey for providing Ptch constructs, U. Kurzik-Dumke and M. Rozakis-Adcock for anti-Tid1 antibodies, E. Epstein and numerous colleagues for discussions and comments, R. del Rosario for assistance with animal husbandry, and N. Killeen and the UCSF transgenic core facility for assistance in the generation of transgenic mice. This work was supported by grants from the National Cancer Institute and the Department of Energy Low Dose Program. A.B. acknowledges support from the Barbara Bass Bakar Chair of Cancer Genetics.
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Wakabayashi, Y., Mao, JH., Brown, K. et al. Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice. Nature 445, 761–765 (2007). https://doi.org/10.1038/nature05489
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DOI: https://doi.org/10.1038/nature05489
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