EVIDENCE FOR A COMMON GENETIC PATHWAY CONTROLLING SUSCEPTIBILITY TO MOUSE SKIN TUMOR PROMOTION BY DIVERSE CLASSES OF PROMOTING AGENTS

The present study has compared different mouse stocks and strains with known sensitivity to phorbol ester skin tumor promotion for their sensitivities to skin tumor promotion by a prototypic organic peroxide (benzoyl peroxide, BzPo) and anthrone (chrysarobin, Chr) tumor promoter. Following initiation with either 7,12-dimethylbenz(a)anthracene and/or N-methyl-N'-nitro-N-nitrosoguanidine, groups of mice were promoted with several different doses of each promoting agent. Among mice selectively bred for sensitivity to phorbol ester promotion, the order of sensitivity to BzPo was inbred SENCAR (SSIn) > SENCAR > CD-1. With Chr as the promoter, the order of sensitivity was SENCAR > SSIn > CD-1. Concurrent tumor promotion experiments examined the responsiveness of two common inbred mouse strains, DBA/2 and C57BL/6. The phorbol ester-responsive mouse strain, DBA/2, was more sensitive to skin tumor promotion by Chr than was C57BL/6 at all doses tested but was clearly less sensitive than both SENCAR and SSIn mice. Finally, DBA/2 and C57BL/6 mice were similar in their responsiveness to BzPo promotion, but again both of these inbred strains were significantly less sensitive than were SSIn and SENCAR mice to this organic peroxide type of skin tumor promoter. Histological evaluations comparing SENCAR and C57BL/6 mice revealed that a major difference between these strains in response to multiple Chr and BzPo treatments was in the inflammatory response (measured by edema formation). Unlike 12-O-tetradecanoylphorbol-13-acetate, Chr and BzPo did not induce dramatic differences in the epidermal hyperplasia (as measured by epidermal thickness) in these two mouse lines. The results presented in this paper suggest that there is a common pathway controlling susceptibility to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate, BzPo, and chrysarobin. These results are discussed in terms of a possible genetic model(s) for skin tumor promotion in mice.