Androgens Modify Skin Formation and DMBA-Induced Pathology in Mice (#69)
Epidemiological studies show significantly more non-melanoma skin cancers in men than in women, suggesting a role for sex steroid hormones. Androgen receptor (AR) is widely distributed at different layers of the skin suggesting tissue specific effects of androgens via AR in the skin. This is consistent with diverse modifications of skin morphology by endogenous or exogenous androgens. Yet, the role of androgens acting via AR in skin structural development as well as in experimental skin carcinogenesis is not well understood.
We used the androgen insensitive, AR knockout (ARKO; Cre/loxP global inactivation) mouse model to determine the role of AR in 7,12dimethylbenz[a]anthracene (DMBA)-induced experimental skin cancer. Male and female wild-type (WT) and ARKO mice were treated with 1mg DMBA/week (in 100μl sesame oil) for 6 weeksfrom 8 weeks of age. We demonstrate that males were significantly (p<0.05) more susceptible to DMBA-induced experimental skin cancer than females and AR inactivation significantly delayed cancer detection in both male (median time to palpable cancer 21 vs 30 weeks, p=0.0014) and female mice (27 vs >35 weeks, p=0.009).
To determine if the AR inactivation modified skin structure at the time of DMBA exposure, skin from 8 week old intact male and female WT and ARKO mice was analysed for epidermis and dermis thickness and thickness of collagen layer. Compared to females, males had thicker dermis (337±35 vs 229±21µm in WT [mean±SE; n≥3; p=0.003] and 243±11 vs 185±9µm in ARKO [n≥5; p=0.031]) and collagen layer (323±33 vs 203±14µm in WT [n=3; p=0.004] and 230±22 vs 146±8µm in ARKO [n=3; p=0.023]). AR inactivation significantly reduced thickness of dermis (p=0.003) and collagen (p=0.015) layers compared to WT in males only. Epidermis thickness (p=0.226, ANOVA) was similar among all mice.
In conclusion, we demonstrate that androgen action operating via AR accelerate progression of experimental skin cancer and have a significant role in skin structural development.