Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice

Yuichi Wakabayashi, Jian-Hua Mao, Ken Brown, Michael Girardi and Allan Balmain ()
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Yuichi Wakabayashi: Cancer Research Institute, University of California at San Francisco, 2340 Sutter Street, San Francisco, California 94143, USA
Jian-Hua Mao: Cancer Research Institute, University of California at San Francisco, 2340 Sutter Street, San Francisco, California 94143, USA
Ken Brown: University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
Michael Girardi: Yale University School of Medicine, New Haven, Connecticut 06520, USA
Allan Balmain: Cancer Research Institute, University of California at San Francisco, 2340 Sutter Street, San Francisco, California 94143, USA

Nature, 2007, vol. 445, issue 7129, 761-765

Abstract: 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.

Date: 2007
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DOI: 10.1038/nature05489

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