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

Sep 22, 2026

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Men have a higher risk of developing cutaneous squamous cell carcinoma (SCC) than women, yet sex-specific signaling pathways remain insufficiently modeled. Using a UV-induced SCC model in hairless mice, the study shows enhanced SCC development in males despite similar UV DNA damage. It identifies E2F transcription factors as key sex-specific proliferative markers, with estrogen receptor–mediated selective downregulation of E2F1/2 and CDKN3 after UV exposure in female epidermis. CDKN3 depletion limits S-phase progression, reduces tumor growth in xenografts, and aligns with better prognosis in female head and neck SCC.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages28

Reading Time1 h 11 min

AccessFree to download

Introduction

Sex differences in cancer incidence and mortality

Sexual dimorphism in cutaneous squamous cell carcinoma

Role of sex hormones and UV-driven DNA damage

DNA damage response and cell cycle regulation

Article An estrogen receptor/E2F1/CDKN3 axis protects from UV-induced skin cancers in females Céline Lukowicz 1 ✉, Carine Winkler 1, Catherine Roger1, Joanna C Fowler 2, Yi-Chien Tsai3,4, Joachim Meuli 5, Stéphanie Claudinot 1, Yun-Tsan Chang 3,4, Christoph Iselin3, Philip H Jones 2,6, Emmanuella Guenova3,4,7, Paris Jafari1 & Liliane Michalik 1 ✉ Abstract 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 sextargeted preventive and therapeutic strategies in SCC. Keywords UV-induced Squamous Cell Carcinoma; Skin; Proliferation; Estrogen Receptors; E2F Transcription Factors Subject Categories Cancer; Cell Cycle; Chromatin, Transcription & Genomics [https://doi.org/10.1038/s44319-026-00743-2](https://doi.org/10.1038/s44319-026-00743-2) Received 27 January 2025; Revised 6 February 2026; Accepted 27 February 2026 Published online: 24 March 2026 Introduction Differences in the incidence of at least 21 different cancers, excluding reproductive tissues, have been reported between men and women, with men having a greater risk of developing cancer than women (Clocchiatti et al, 2016; Jackson et al, 2022) . This sexdifference also includes cancer mortality worldwide, with death rates 43% higher in men than in women (Sung et al, 2021) . Cutaneous Squamous Cell Carcinoma (SCC), the second most common keratinocyte skin cancer (Que et al, 2018), is also affected by this sexual dimorphism. Indeed, sex is recognized as a risk factor for SCC as important as fair skin or advanced age (Nagarajan et al, 2019), and a recent meta-analysis of cutaneous head and neck SCC reported that men are more commonly affected than women (Tanet al, 2022) . This sex-disparity in SCC prevalence has been mainly attributed to differences in lifestyle (e.g. outdoor work (Szewczyket al, 2018), behavior (e.g. motivation to sun protection measures and men shorter hair preferences (Roberts et al, 2021) and genetics (e.g. common men baldness (Jenkins et al, 2014) related to UV exposure. Beyond sex-differences in the immune system (Buddenet al, 2021; Keller et al, 2010; Ramsay et al, 2003) and in oxidative stress in response to UV exposure (Thomas-Ahner et al, 2007), intrinsic factors and physiological differences remain largely underexplored. In particular, the role of sex hormones in modulating vulnerability to SCC is barely understood. Nevertheless, an elevated risk of developing keratinocyte skin cancers was associated with the use of oral contraceptives and with hormone replacement therapy (Asgari et al, 2010; Li et al, 2023) . Along the same lines, the androgen receptor seems to be a key determinant of melanoma development, another type of skin cancer (Ma et al, 2021) . Besides multiple genes present on sex chromosomes have been proposed to also play a role in oncogenesis (Clocchiatti et al, 2016) . Collectively, these data strongly suggest that sex hormones have a role in modulating SCC incide

FAQs

How does this study model UV-induced SCC sex differences?

It uses a UV-induced SCC model in hairless mice that recapitulates the human sex difference, showing enhanced SCC development in males.

What molecular pathway protects females from UV-induced SCC?

E2F transcription factors drive a sex-specific proliferative response, while estrogen receptors mediate selective downregulation of E2F1/2 and CDKN3 in female epidermis after UV exposure.

What happens when CDKN3 is depleted?

CDKN3 depletion impairs SCC cell progression into S-phase and reduces tumor growth in xenograft models, and low CDKN3 expression in head and neck SCC is associated with female patients and better prognosis.

Sep 22, 2026

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