title: Androgen receptor actions modify skin structure and chemical carcinogen-induced skin cancer susceptibility in mice.
abstract: Men are significantly more susceptible to non-melanoma skin cancers than women, and the androgen receptor (AR) is widely distributed in the skin, suggesting a ro\le for androgens acting via AR. Therefore, we explored the role of androgen action via AR in susceptibility to experimental 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis and in skin structural development of male and female mice. We demonstrate that both the male gender and androgen action via AR modify the susceptibility to carcinogen-induced skin cancer, but the effect depends on the carcinogenesis model used. Following systemic DMBA exposure, 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 tumours 19 vs. >35 weeks (wild-type [WT] vs. AR knockout [ARKO], p < 0.001) and female (27 vs. >35 weeks, p = 0.008)) mice. In contrast, following DMBA/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced multistage local skin carcinogenesis, AR inactivation protected against formation of DMBA-induced skin cancers in both male and female mice. The skin structure was also affected by gender effect as well as the AR inactivation and could at least partly explain the different responses between the carcinogenesis models (systemic vs. topical). In addition, AR inactivation modified Cox-1 and Cox-2 expression in the skin, suggesting possible molecular mechanism for the AR effect on skin. Finally, some gender differences are observed also in ARKO mice insensitive to androgens, suggesting that factors other than androgens also play a role in gender-dependent skin carcinogenesis.
authors.affiliation: ANZAC Research Institute, Andrology Laboratory, University of Sydney, Sydney, NSW 2139, Australia.
authors.forename: Ulla
authors.initials: U
authors.lastname: Simanainen
authors.forename: Tegan
authors.initials: T
authors.lastname: Ryan
authors.forename: Desmond
authors.initials: D
authors.lastname: Li
authors.forename: Francia Garces
authors.initials: FG
authors.lastname: Suarez
authors.forename: Yan Ru
authors.initials: YR
authors.lastname: Gao
authors.forename: Geoff
authors.initials: G
authors.lastname: Watson
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Wang
authors.forename: David J
authors.initials: DJ
authors.lastname: Handelsman
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage; D003094:Collagen / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004198:Disease Susceptibility; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009367:Neoplasm Staging; D009374:Neoplasms, Experimental; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*
chemical_list: D000728:Androgens; D002273:Carcinogens; D011944:Receptors, Androgen; D003094:Collagen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2