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Decreased susceptibility to NMU-induced mammary carcinogenesis in transgenic rats carrying multiple copies of a rat ras gene driven by the rat Harvey ras promoter

Abstract

Ras protein over-expression has been observed in human breast cancers although the significance of Ras over-expression in the etiology of breast cancer is unknown and its contribution to breast cancer prognosis is still debated. In this study, the over-expression of both wild-type Harvey and Kirsten Ras proteins as contributors to rat mammary carcinogenesis were examined using a transgenic rat model. Three rat transgenic lines (designated HrHr transgenics) carrying three to six copies of wild-type rat Harvey ras driven by the wild-type rat Harvey ras promoter were produced. In addition, transgenic lines carrying either three or seven copies of the Kirsten ras gene under the same promoter (HrKr) were produced. No pathological changes in the mammary gland were observed in any of the HrHr or HrKr transgenic rat line heterozygotes. Two of the Ras transgenic lines, HrHr (R8) and HrKr (4334), had a significant reduction in NMU-induced rat mammary cancer when compared to their non-transgenic littermates. All five Ras transgenic lines developed fewer carcinomas than their non-transgenic littermates following NMU exposure. The percentage of NMU-induced G35 to A35 activating mutations in the endogenous Harvey ras gene in mammary carcinomas from the HrHr, HrKr transgenic rats and their non-transgenic littermates was similar (50%). In contrast, less than 1% of the NMU-induced carcinomas in these Ras transgenic rats had an activating ras mutation in their transgenes. These findings highlight the potential of Ras to function as a modifier gene in repressing mammary carcinogenesis.

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Acknowledgements

NIH Grant CA77527 supported this study. T Thompson was the recipient of Department of Defense Breast Cancer Fellowship DAMD17-94-J-4104. The authors are grateful to D MacKenzie for critical reading of this manuscript. The authors would also like to thank the excellent technical assistance provided by W Kennan, M Gheen, J Houtman, and P McGuire. pNMU-H-ras was kindly provided by M Barbacid and a plasmid construct containing 3800 bp upstream of the rat Harvey ras coding region was generously provided by P Duesberg. S Wu of the UWCCC Cytogenetics Facility performed FISH analysis. This paper is dedicated to J Lohse (Heideman), who pioneered techniques used for the development of transgenic rats.

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Correspondence to Michael N Gould.

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Thompson, T., Haag, J., Lindstrom, M. et al. Decreased susceptibility to NMU-induced mammary carcinogenesis in transgenic rats carrying multiple copies of a rat ras gene driven by the rat Harvey ras promoter. Oncogene 21, 2797–2804 (2002). https://doi.org/10.1038/sj.onc.1205391

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