Journal Article

Modulation of basal and squamous cell carcinoma by endogenous estrogen in mouse models of skin cancer

M. Mancuso, D. Gallo, S. Leonardi, M. Pierdomenico, E. Pasquali, I. De Stefano, S. Rebessi, M. Tanori, G. Scambia, V. Di Majo, V. Covelli, S. Pazzaglia and A. Saran

in Carcinogenesis

Volume 30, issue 2, pages 340-347
Published in print February 2009 | ISSN: 0143-3334
Published online October 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgn243
Modulation of basal and squamous cell carcinoma by endogenous estrogen in mouse models of skin cancer

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Patched1 heterozygous mice (Ptch1+/−) are useful for basal cell carcinoma (BCC) studies, being remarkably susceptible to BCC induction by ultraviolet or ionizing radiation. Analogously, skin carcinogenesis-susceptible (Car-S) mice are elective for studies of papilloma and squamous cell carcinoma (SCC) induction. We previously reported a striking effect of gender on BCC induction in Ptch1+/− mice, with total resistance of females; likewise, Car-S females show increased skin tumor resistance relative to males. Here, we investigated the protective role of endogenous estrogen in skin keratinocyte tumorigenesis. Control (CN) and ovariectomized Ptch1+/− or Car-S females were irradiated for BCC induction or topically treated with chemical carcinogens for SCC induction. Susceptibility to BCC or SCC was dramatically increased in ovariectomized Ptch1+/− and Car-S females and restored to levels observed in males. Remarkably, progression of initially benign papillomas to malignant SCC occurred only in ovariectomized Car-S females. We explored the mechanisms underlying tumor progression and report overexpression of estrogen receptor (ER)-α, downregulation of ERβ and upregulation of cyclin D1 in papillomas from ovariectomized Car-S relative to papillomas from CN females. Thus, an imbalanced ERα/ERβ expression may be associated with estrogen-mediated modulation of non-melanoma skin carcinogenesis, with a key role played by cyclin D1. Our findings underscore a highly protective role of endogenous estrogen against skin tumorigenesis by diverse agents in two independent mouse models of skin cancer.

Journal Article.  5999 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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