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Increased sensitivity to two-stage skin carcinogenesis of mice heterozygous for the repeated epilation mutation (Er)
1Department of Medicine, University of Washington, Seattle 98195.
Abstract:
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.
Insights
Mice with the repeated epilation (Er) mutation show increased susceptibility to skin papillomas. These Er/+ mice developed tumors even without promotion, unlike normal mice, indicating a link between hair loss defects and skin tumor development.
Area of Science:
- Dermatology
- Oncology
- Genetics
Background:
- Mice heterozygous for the repeated epilation (Er) mutation exhibit cutaneous abnormalities and spontaneous hair loss.
- BALB/c mice are typically resistant to chemically induced skin cancers.
- The Er mutation's impact on skin tumor development in a BALB/c background is not well understood.
Purpose of the Study:
- To investigate the susceptibility of Er/+ heterozygous mice on a BALB/c background to spontaneous and induced skin tumors.
- To compare the development and characteristics of skin papillomas in Er/+ mice versus wild-type (+/+) mice.
Main Methods:
- Er/+ mice and their wild-type (+/+) littermates were subjected to a skin carcinogenesis protocol using 7,12-dimethylbenz(a)anthracene (DMBA) initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion.
- Tumor development, latency, frequency, and type (promoter-dependent vs. promoter-independent) were monitored and compared between genotypes.
Main Results:
- Er/+ mice developed papillomas following DMBA initiation even without TPA promotion, a response not observed in +/+ mice.
- While tumor incidence was similar after 15 weeks of TPA promotion, Er/+ mice showed a higher number of papillomas.
- Papillomas in Er/+ mice were qualitatively different, with a greater proportion being promoter-independent, persisting after promotion cessation.
Conclusions:
- The Er mutation confers increased susceptibility to skin papilloma development in mice.
- Skin defects associated with the Er mutation influence the mode of skin tumor development, promoting promoter-independent papillomas.
- These findings highlight a connection between genetic mutations causing hair loss and altered responses to chemical carcinogens.