Increased sensitivity to two-stage skin carcinogenesis of mice heterozygous for the repeated epilation mutation (Er).

Mice heterozygous for repeated epilation mutation (Er) have cutaneous abnormalities that result in repeated loss of hair. Skin papillomas and carcinomas occur spontaneously in such Er/+ mice. BALB/c mice are generally resistant to induced skin cancers. We investigated whether Er/+ heterozygous mice of BALB/c genetic background exhibit increased susceptibility to spontaneous and induced skin tumors. Although none of the Er/+ CXB(N5) mice spontaneously developed skin tumors, they exhibited increased sensitivity to the development of skin papillomas induced by an initiation-promotion regimen. Er/+ mice developed papillomas after 20 micrograms DMBA initiation in the absence of TPA promotion, but the same dose of DMBA was subtumorigenic in +/+ (sibling) mice. Although 15 weeks of TPA promotion resulted in similar tumor susceptibilities, tumor latencies and tumor frequencies in the 2 groups of initiated mice, the papillomas were qualitatively different. Er/+ mice developed more papillomas of the delayed promoter-independent type, which occur after termination of promotion. In contrast, +/+ mice developed more promoter-dependent papillomas, which regress after termination of promotion. Therefore Er/+ mice had a significantly higher number of papillomas than +/+ mice at the termination of the experiment. These results suggest that Er-mutation-induced skin defects not only lead to the repeated loss of hair, but also influence the mode of development of skin papillomas from carcinogen-initiated cells.