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.

Description

Acknowledgements: We thank the Animal facility (Center of Integrative Genomics, University of Lausanne, Switzerland) for expert technical assistance and the Genomic Technologies Facility (University of Lausanne, Switzerland) for performing RNA-seq analyses. We thank Fabienne Lammers (Center for Integrative Genomics, University of Lausanne, Switzerland) for mouse genotyping and Nathalie Hirt (Lausanne University Hospital, University of Lausanne, Switzerland) for valuable support in getting human skin samples from the Lausanne University Hospital biobank. We are grateful to Prof. Hon. Béatrice Desvergne (University of Lausanne, Switzerland) and Hervé Guillou, PhD, Laurence Payrastre, PhD and Sandrine Ellero-Simatos, PhD (Toxalim, INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, University of Toulouse, France) and Alexandra Montagner, PhD (I2MC, UMR1297, INSERM/UPS), Dorian Ziegler, PhD and Sarah Geller, PhD (Center of Integrative Genomics, University of Lausanne, Switzerland) for constructive scientific discussion. This work was supported by the Swiss National Science Foundation (IZLIZ3_200253/1 to EG), the Foundation Recherche Cancer ISREC (CCP 10-3224-9 to EG), and the Etat de Vaud (University of Lausanne; SKINTEGRITY.CH collaborative research to EG and LM).

Funder: Skintegrity.ch

Keywords

UV-induced Squamous Cell Carcinoma, Skin, Estrogen Receptors, E2F Transcription Factors, Proliferation

Journal Title

EMBO Reports

Journal ISSN

1469-3178

Volume Title

27

Publisher

Nature Publishing Group UK

Publisher DOI

https://doi.org/10.1038/s44319-026-00743-2

Rights and licensing

Except where otherwised noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/

Sponsorship

Swiss National Science Foundation (IZLIZ3_200253/1)
Foundation Recherche Cancer ISREC (CCP 10-3224-9)

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