Estrogen Receptors/E2F1/CDKN3 Axis Protects from UV-induced Skin Cancers in Females

Men have a significantly higher risk of developing cutaneous squamous cell carcinoma (SCC) compared to women, but models and comprehensive analysis of signaling pathways highlighting this sexual dimorphism are missing. In this study, we display a UV-induced SCC model in hairless mice recapitulating this sex difference, with enhanced SCC development in males. While UV-induced DNA damage is similar between sexes, we uncovered sex-specific responses in epidermal cell proliferation and differentiation. Using global transcriptional profile analyses, we identified E2F transcription factors as key sex-specific markers involved in the proliferative response to UV. Notably, E2F1/2, along with their target gene CDKN3, were selectively downregulated in female mice and human epidermis following UV exposure. Mechanistically, UV-induced and sex-specific modulation of E2F1 and CDKN3 expression is mediated by Estrogen Receptors. Lastly, low levels of CDKN3 in head and neck SCC are observed exclusively in female patients correlating with better prognosis. These findings shed new light on fundamental mechanisms protecting women from cancer after carcinogen exposure and could lead to better sex-targeted preventive and therapeutic strategies in SCC and other malignancies.