Why Are Women Better Protected Against UV-Induced Skin Cancers?

Men develop cutaneous squamous cell carcinomas more often than women, but the biological reasons behind this difference remained poorly understood. A recent breakthrough reveals a protective mechanism specific to women, involving estrogen receptors and a key protein in the cell cycle.

Researchers observed that ultraviolet exposure triggers distinct reactions depending on sex. In male mice, UV mainly stimulates the proliferation of epidermal cells, thus promoting the formation of precancerous lesions and tumors. In females, however, UV disrupts cell differentiation more, leading to more pronounced epidermal atypia in the short term, but better long-term recovery. These differences are not explained by greater DNA damage, which is similar in both sexes, but by how cells respond to these aggressions.

Analysis of genes activated after UV exposure showed that E2F family transcription factors, which regulate cell division, are less active in females. Specifically, estrogen receptors reduce the expression of E2F1 and its target CDKN3, a protein that normally accelerates cell cycle progression. This reduced activity limits tumor growth. In female mice exposed to UV, CDKN3 is less present in the epidermis and tumors, slowing their development. Conversely, males maintain high levels of CDKN3, promoting cell proliferation and worsening lesions.

Experiments on human skin samples and carcinoma biopsies confirm these findings. Women exhibit lower expression of CDKN3 after UV exposure, and this trait is associated with a better prognosis in patients with head and neck carcinomas. By artificially reducing CDKN3 in human cancer cells, scientists also observed a slowdown in tumor growth in mice, confirming its role in cancer progression.

These discoveries suggest that estrogens modulate the skin’s response to UV by acting on E2F1 and CDKN3, providing natural protection for women. They pave the way for preventive and therapeutic strategies specifically targeting these mechanisms by sex, to better combat sun-induced skin cancers.

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Official Study Source

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

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

Journal: EMBO Reports

Publisher: Springer Science and Business Media LLC

Authors: Céline Lukowicz; Carine Winkler; Catherine Roger; Joanna C Fowler; Yi-Chien Tsai; Joachim Meuli; Stéphanie Claudinot; Yun-Tsan Chang; Christoph Iselin; Philip H Jones; Emmanuella Guenova; Paris Jafari; Liliane Michalik