Human are continually exposed to a wide variety of chemicals, some of which may act as initiators, promoters, cocarcinogens and/or complete carcinogens. Current evidence suggests that tumor promotion plays an important role in the etiology of human cancer. The proposed research is designed to investigate the genetic factors controlling susceptibility to skin tumor promotion by phorbol esters in inbred mouse strains. Mouse skin is a well known target tissue for phorbol ester tumor promoters and is a widely studied model system for skin carcinogenesis.
The specific aims of the proposal are to determine the susceptibility of B6D2F1 mice, compared to the two parental strains (C57BL/6 and DBA/2) to skin tumor promotion by 12-0-tetradecanoylphorbol-13-acetate (TPA). Our preliminary work indicates that DBA/2 mice are highly sensitive to phorbol ester skin tumor promotion. The susceptibility of backcrossses with the resistant parent (i.e., B6D2F1 X C57BL/6) and F2 mice, to skin tumor promotion by TPA will also be investigated. We will also determine the extent to which TPA-induced epidermal hyperplasis, inflammation, and dark basal keratinocyte appearance correlates with susceptibility to skin tumor promotion in the parental strains and backcross mice. Furthermore, we will examine the allelic composition of B6D2F1 X C57BL/6 backcross mide for 13 biochemical genetic markers on 10 different chromosomes to obtain evidence of gene linkage. The susceptibility of 15 BXD recombinant inbred strains to skin tumor promotion by TPA will be determined. Finally, we will attempt to identify other strains of mice with high susceptibility to skin tumor promotion by TPA. This approach will allow us to test the hypothesis that a single gene locus controls susceptibility to skin tumor promotion by TPA in DBA/2 mice.
