Humans 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 the tumor promotion stage of carcinogenesis plays an important role in the etiology of human cancer. The proposed research is designed to further investigate the genetic factors controlling susceptibility to skin tumor promotion by phorbol esters and other classes of tumor promoters in inbred mouse strains. Mouse skin is a well known target tissue for many classes of promoters including phorbol ester tumor promoters and is a widely studied model system for skin carcinogenesis.
The specific aims are: 1) to further explore the number of genes controlling susceptibility to skin tumor promotion by phorbol esters in DBA/2 C3H/He,SSIn, C57BL/6, and other inbred mouse strains as follows; a) to examine all available BXD RI strains for sensitivity to TPA promotion; b) to examine the sensitivity of B6C3F2, B6C3F1 x C57BL/6 (backcross), B6SSInF1, B6SSInF2,and B6SSInF1 x C57BL/6 (backcross) mice to TPA promotion; c) to examine all available BXH RI strains for sensitivity to TPA promotion; and d) to continue to look for linkage in an attempt to map TPA promotion sensitivity genes (see also #'s 3 and 4 below). 2) To determine the relative responsiveness of DBA/2, C57BL/6 mice (and possibly other inbred strains) to different classes of skin tumor promoting agents including indole alkaloids, polyacetates, anthrones, and organic peroxides. 3) To determine whether differences exist in the metabolism of phorbol esters between inbred strains of mice; and 4) to determine whether differences exist between inbred strains of mice with regard to the phorbol ester receptor system (i.e., protein kinase C(PKC)), for: a) epidermal expression of isozymes of PKC; b) binding characteristics of TPA, teleocidin, diacylglycerols and possible other derivatives to epidermal PKC isozymes; c) translocation of epidermal PKC from cytosol to membrane; and d) PKC isozyme down modulation. This approach will allow us to test the hypothesis that at least two gene loci control susceptibility to skin tumor promotion by TPA in DBA/2 mice and that at least one of these genes is related to phorbol ester metabolism such as an esterase and/or the phorbol ester receptor, PKC.
