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Interactions between wild-type and mutant Ras genes in lung and skin carcinogenesis

Oncogene volume 32, pages 4028–4033 (2013)Cite this article

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Abstract

Ras oncogenes (Hras, Kras and Nras) are important drivers of carcinogenesis. However, tumors with Ras mutations often show loss of the corresponding wild-type (WT) allele, suggesting that proto-oncogenic forms of Ras can function as a suppressor of carcinogenesis. In vitro studies also suggest that WT Ras proteins can suppress the tumorigenic properties of alternate mutant Ras family members, but in vivo evidence for these heterologous interactions is lacking. We have investigated the genetic interactions between different combinations of mutant and WT Ras alleles in vivo using carcinogen-induced lung and skin carcinogenesis in mice with targeted deletion of different Ras family members. The major suppressor effect of WT Kras is observed only in mutant Kras-driven lung carcinogenesis, where loss of one Kras allele led to increased tumor number and size. Deletion of one Hras allele dramatically reduced the number of skin papillomas with Hras mutations, consistent with Hras as the major target of mutation in these tumors. However, skin carcinoma numbers were very similar, suggesting that WT Hras functions as a suppressor of progression from papillomas to invasive squamous carcinomas. In the skin, the Kras proto-oncogene functions cooperatively with mutant Hras to promote papilloma development, although the effect is relatively small. In contrast, the Hras proto-oncogene attenuated the activity of mutant Kras in lung carcinogenesis. Interestingly, loss of Nras increased the number of mutant Kras-induced lung tumors, but decreased the number of mutant Hras-induced skin papillomas. These results show that the strongest suppressor effects of WT Ras are only seen in the context of mutation of the cognate Ras protein, and only relatively weak effects are detected on tumor development induced by mutations in alternative family members. The data also underscore the complex and context-dependent nature of interactions between proto-oncogenic and oncogenic forms of different Ras family members during tumor development.

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Acknowledgements

We are grateful to Dr Motoya Katsuki and Dr Hiroki Nagase for the HrasKO mice, and Dr Tyler Jacks for the LSL-KrasG12D mice. This work was supported by NCI Grants CA111834-01 and CA84244 to AB. PMKW is supported by NIH Training Grant T32 GM007175 and a National Science Foundation Graduate Research Fellowship. MDT acknowledges the support from the Nan Tucker McEvoy Research Fund in Thoracic Oncology. AB acknowledges support from the Barbara Bass Bakar Chair in Cancer Genetics.

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Authors and Affiliations

  1. Department of Surgery, Thoracic Oncology Program, University of California San Francisco, San Francisco, CA, USA

    M D To

  2. Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, USA, CA

    M D To, R D Rosario, P M K Westcott, K L Banta & A Balmain

  3. Pharmaceutical Sciences and Pharmacogenomics Program, University of California San Francisco, San Francisco, CA, USA

    P M K Westcott & A Balmain

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  1. M D To
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  2. R D Rosario
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  4. K L Banta
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  5. A Balmain
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Correspondence to M D To or A Balmain.

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To, M., Rosario, R., Westcott, P. et al. Interactions between wild-type and mutant Ras genes in lung and skin carcinogenesis. Oncogene 32, 4028–4033 (2013). https://doi.org/10.1038/onc.2012.404

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