Further genetic analyses of skin tumor promoter susceptibility using inbred and recombinant inbred mice.

To explore further the genetics of susceptibility to skin tumor promotion in inbred mice, several aspects of responsiveness to 12-O-tetradecanoylphorbol-13-acetate (TPA) were examined in C3H/He mice and segregating crosses between this mouse strain and C57BL/6 mice as well as BXD and BXH recombinant inbred (RI) strains. Dose-response relationships were established for skin tumor promotion by TPA following initiation with 7,12-dimethylbenz[a]anthracene in C3H/He and B6C3F1, as well as several other mouse stocks and strains included for comparison. The relative responsiveness to TPA skin tumor promotion was: SENCAR much greater than DBA/2 greater than C3H/He approximately B6D2F1 greater than B6C3F1 much greater than C57BL/6. Analyses of the susceptibility of B6C3F2 and B6C3F1 x C57BL/6 backcross mice suggested that a minimum of two dominant genetic loci control responsiveness to phorbol ester promotion in these mice. Further analysis of BXH and BXD RI strains suggested the presence of four distinct promotion-responsive phenotypes controlled by a minimum of two genetic loci. The existence of a 'hyper-responsive' phenotype in the sets of RI strains, however, suggests that a third, recessive locus also may play a role in controlling responsiveness to TPA promotion. At 48 h after the last of four applications of TPA, marked hyperplasia and an increase in dark basal keratinocytes were observed in C3H/He mice, whereas in B6C3F1 mice the response in these parameters was intermediate between C3H/He and C57BL/6 mice. A marked dermal inflammation, as determined by infiltration of polymorphonuclear cells, was observed in C3H/He and B6C3F1 mice, whereas little was noted in C57BL/6 mice. Furthermore, histological evaluations of selected BXD RI strains revealed a significant correlation between the magnitude of the hyperplasia response and the percentage of mice bearing tumors. The present data, in conjunction with our previous studies, confirm that the major gene(s) controlling susceptibility to tumor promoter induced by TPA in two sensitive strains (i.e. DBA/2 C3H/He) are similar or closely linked to those for induction of sustained hyperplasia. In addition, the present data provide new evidence for a model where allelic differences at a minimum of three loci contribute to gene differences in susceptibility to phorbol ester promotion DBA/2 and C3H/He versus C57BL/6 mice.