An estrogen receptor/E2F1/CDKN3 axis protects from UV-induced skin cancers in females

Men have a higher risk of developing cutaneous squamous cell carcinoma (SCC) compared with women, but models and comprehensive analyses of signaling pathways highlighting this sexual dimorphism are missing. Here, we use 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 uncover sex-specific responses in epidermal proliferation and differentiation. Global transcriptional profiling identifies E2F transcription factors as key sex-specific markers of the proliferative response to UV. E2F1/2 and their target gene CDKN3 are selectively downregulated in female mouse and human epidermis following UV exposure, and this is mediated by estrogen receptors. CDKN3 depletion impairs SCC cell progression into S-phase and reduces tumor growth in xenograft models. Consistently, low CDKN3 expression in head and neck SCC occurs exclusively in female patients and correlates with better prognosis. We thus reveal a mechanism protecting women from carcinogen-induced cancer formation, which could lead to better sex-targeted preventive and therapeutic strategies in SCC.