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

Abstract

We report on bidirectional selective breeding, initiated from a genetically defined foundation population and carried out to selection limit, for producing lines of mice endowed with maximal resistance (Car‐R) or maximal susceptibility (Car‐S) to 2‐stage skin tumorigenesis. The initial population resulted from a balanced intercrossing of 8 inbred strains of mice. The tumors, induced by a single application of DMBA (initiation) and twice weekly applications 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 malignant carcinomas. The Car‐R line was selected through a strong challenge, while the Car‐S line selection was based on responses to decreasing concentrations of DMBA and TPA. The selection limit was reached after 14 or 15 generations showing progressive interline divergence, which strongly suggests the interaction of several quantitative trait loci (QTL). The phenotypic difference 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 were 100 and 40 times lower, respectively. The mean heritability realized during 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 to carcinoma induction. An association of coat color with tumorigenesis was observed in interline F2 segregants. The Car‐R and Car‐S lines, obtained through a long‐lasting breeding program, are a unique model for identifying the QTL involved in chemical tumorigenesis and will be provided to interested investigators. Int. J. Cancer 88:424–431, 2000. © 2000 Wiley‐Liss, Inc.

Inhibition of both skin and lung tumorigenesis by Car‐R mouse‐derived cancer modifier loci

“…1,2 The Car mice interline difference in susceptibility is Ͼ100-fold. 3 Tumor susceptibility and resistance in the Car lines were initially considered skin tissue-specific, because there was no interline difference in sarcoma induction by subcutaneous injection of chemical carcinogens. 4 In our present study, we tested the hypothesis that Car-R mice carry cancer resistance loci that inhibit susceptibility to both skin and lung tumorigenesis.…”

“…4 In our present study, we tested the hypothesis that Car-R mice carry cancer resistance loci that inhibit susceptibility to both skin and lung tumorigenesis. Tumors were initiated in SWR/J mice, which are highly susceptible to both lung and skin cancer 3 and in Car-R and (SWR/JxCar-R)F1 mice using urethane, a multi-organ carcinogen that can initiate both lung and skin tumorigenesis. 5,6 Analysis of urethane-initiated and TPA-promoted Car-R, SWR/J and (SWR/JxCar-R)F1 mice revealed resistance to both skin and lung carcinogenesis in the Car-R line and F1 hybrids, showing that the genetic resistance of Car-R mice to both tumor types is dominant over the susceptibility of the SWR/J strain.…”

Modulation of Patched -Associated Susceptibility to Radiation Induced Tumorigenesis by Genetic Background

“…A colony was established in the animal facility at ENEA Casaccia (Rome, Italy) by crossing Ptch1 neo67/ϩ heterozygous males with CD1-wildtype (wt) females. Generation of Car-R and Car-S lines of mice has been described (17). For study of genetic background effects, Ptch1 neo67/ϩ heterozygous males on CD1 background were crossed to Car-S and Car-R females to generate F1SPtch1 neo67/ϩ and F1RPtch1 neo67/ϩ heterozygotes, respectively, and wt F1S and F1R mice.…”

“…As a first step toward identification of genes that control susceptibility to BCC tumorigenesis, Ptch1 neo67/ϩ mice on CD1 background were crossed with carcinogenesis-resistant (Car-R) and carcinogenesis-susceptible (Car-S) lines of mice, generated in our laboratory by phenotypic selection for high susceptibility or resistance to inducers of skin cancers starting from a cross of eight parental inbred strains (16,17). Sixteen consecutive generations of selective breeding produced an interline difference in susceptibility Ͼ100-fold.…”

Loss of tyrosinase activity confers increased skin tumor susceptibility in mice

“…These genetically heterogeneous outbred mice provide high-resolution mapping and placed the peak LOD score for the Chromosome 7 locus in a o5.5 cM region near the Tyr gene (Peissel et al, 2001). Moreover, all the tumor susceptible Car-S mice are albino and carry, in a 6 cM region that included the Tyr locus, a specific haplotype identical by descend to that of albino progenitor strains, whereas resistant Car-R mice show heterogeneous haplotype and pigmented coat colors (Peissel et al, 2000;Saran et al, 2000). The susceptibility allele of the Car-R/Car-S locus derives from the albino Car-S line and shows a recessive inheritance pattern (Peissel et al, 2001).…”