Susceptibility to phorbol ester skin tumor promotion in (C57BL/6×DBA/2) F1 mice is inherited as an incomplete dominant trait: evidence for multi-locus involvement

Publisher Website
Google Scholar
Abstract
Since current evidence suggests that the tumor promotion stage is a primary determinant in susceptibility to multistage carcinogenesis, we have characterized the genetics of susceptibility to phorbol ester skin tumor promotion in inbred mice. Susceptibility of hybrids (B6D2F 1 ), beween DBA/2 (sensitive) and C57BL/6 (resistant) parents, initiated with N -methyl- N '-nitro- N -nitrosoguanidine (MNNG) and promoted with 12- O -tetradecanoylphorbol-13-acetate (TPA) was similar to DBA/2 mice at doses of 13.6 nmol per mouse but clearly less when doses of 1.7–6.8 nmol per mouse were used. In addition, no significant differences were observed between male andfemale B6D2F 1 mice in terms of tumor incidence although some differences were observed in tumor multiplicities between male and female F 1 mice at the highest TPA dose. Reciprocal F 1 mice initiated with DMBA (i.e. D2B6F 1 ) were also responsive to TPA. Female D2B6F 1 mice were of lower sensitivity at lower doses of TPA, compared to female DBA–2, a finding similar to that observed with B6D2F 1 mice initiated with MNNG. Further analyses of the susceptibility of B6D2F 2 and B6D2F 1 ×C57BL–6 backcross mice to TPA promotion indicated that more than one dominant genetic locus must account for the differences in promotion sensitivity between DBA/2 and C57BL/6 mice. To understand further the genes responsible for promotion sensitivity, histologkal evaluations were performed on DBA/2, C57BL/6 and B6D2F 1 mice. Histological examination revealed that the epidermis of DBA/2 mice showed a marked hyperplasia and the presence of a much greater number of dark basal keratinocytes (DCs) compared with C57BL/6 mice 48 h after the last of four applications of TPA (doses ≥ 3.4 nmol). A marked dermal infiltration of polymorphonuclear leukocytes (PMNs) was observed in DBA/2 mice, whereas little infiltration was observed in the skin of C57BL/6 mice. The hyperplasia in the skin of B6D2F 1 mice was intermediate between DBA/2 and C57BL/6 mice at all TPA doses examined except the lowest dose (1.7 nmol), whereas the DC response, although significantly lower at doses of 6.8 nmol or below, was similar to DBA/2 mice at higher TPA doses (13.6 and 17.0 nmol). The infiltration of PMNs in the dermis of B6D2F 1 mice was similar to or greater than DBA/2 mice at all doses of TPA tested. Our results suggest that (i) susceptibility to TPA promotion is inherited as an incomplete dominant trait; (ii) neither cytoplasmic genetic determinants nor the X-chromosome appear to play a significant role in susceptibility to TPA; and (iii) the degree of sustained epidermal hyperplasia and especially the induction of DCs after multiple applications of TPA show an excellent correlation with inherited susceptibility to promotion. Our data are consistent with a model where allelic differences at more than one genetic locus contribute to the sensitivity of DBA/2 mice to phorbol ester promotion.

This publication has 22 references indexed in Scilit: