Sex_specificity_in_the_epidermal_skin_response_to_UV_exposure_

Men have greater risk to develop cutaneous squamous cell carcinoma (cSCC) than women. UV-light is recognized as the major carcinogen for these cancers but its gender-specific effects have never been characterized. Here, we show that the SKH Hairless mice is an excellent model to study sex-dimorphism in the development of UV-induced cSCC. As with patients, we observe that male mice develop more numerous and aggressive cSCC than female mice. Yet, they exhibit less severe epidermal atypia than females in response to an acute dose of UV.? While the direct impact of UV on epidermal DNA was similar in both sex, we observe sex-specific proliferation, differentiation, and transcriptional responses of epidermal cells. In particular, the expression of the transcription factors E2F1 and E2F2 was down-regulated only in female epidermis in response to UV, as well as their activity, as evidenced by the reduced expression of their target genes Cdkn3 and Cdc25c, two major regulators of cell proliferation known to be overexpressed in numerous cancers. ?Consistent with these data in murine epidermis, we found that CDKN3 expression in patient cSCC is overexpressed only in men. Finally, using women healthy skin explants, we demonstrate that acute exposure to UV also reduces CDKN3 and CDC25C expression. Our study highlights that there are major cellular and molecular differences between male and female epidermis responses to UV and identifies sex-specific key markers. These data will help us understand why women are better protected than men from developing cSCC.