Genetics of chemical carcinogenesis: Analysis of bidirectional selective breeding inducing maximal resistance or maximal susceptibility to 2-stage skin tumorigenesis in the mouse

We report on bidirectional selective breeding, initiated from a genetically defined foundation population and carried out to selection limit, for prod ucing lines of mice endowed with maximal resistance (Car-R) or maximal susc eptibility (Car-S) to 2-stage skin tumorigenesis. The initial population re sulted from a balanced intercrossing of 8 inbred strains of mice. The tumor s, induced by a single application of DMBA (initiation) and twice weekly ap plications of TPA (promotion), were benign papillomas; their number at the end of the promotion period was the phenotype chosen for assortative mating . Afterward, the majority of them regressed while others progressed to mali gnant carcinomas. The Car-R line was selected through a strong challenge, w hile the Car-S line selection was based on responses to decreasing concentr ations of DMBA and TPA. The selection limit was reached after 14 or 15 gene rations showing progressive interline divergence, which strongly suggests t he interaction of several quantitative trait loci (QTL). The phenotypic dif ference was extremely large: the tumor response was 73 times higher in Car- S than in Car-R mice, though the applied concentrations of DMBA and TPA wer e 100 and 40 times lower, respectively. The mean heritability realized duri ng the selective breeding was 0.20 in Car-R and 0.49 in Car-S. Our results are compatible with a minimal QTL estimate of 8 in the Car-R line and of 9 or 10 in the Car-S line. The Car-S line is also much more susceptible Co ca rcinoma induction. An association of coat color with tumorigenesis was obse rved in interline F2 segregants. The Car-R and Car-S lines, obtained throug h a long-lasting breeding program, are a unique model for identifying the Q TL involved in chemical tumorigenesis and will be provided to interested in vestigators. Int. J. Cancer 88:424-431, 2000. (C) 2000 Wiley-Liss. Inc.