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Carcinogenesis Advance Access published online on October 24, 2008
Carcinogenesis, doi:10.1093/carcin/bgn243
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Modulation of Basal and Squamous Cell Carcinoma by Endogenous Estrogen in Mouse Models of Skin Cancer

M. Mancuso1,4, D. Gallo2,4, S. Leonardi1, M. Pierdomenico1, E. Pasquali3, I. De Stefano2, S. Rebessi1, M. Tanori1, G. Scambia2, V. Di Majo1, V. Covelli1, S. Pazzaglia1 and A. Saran1

1 Biotechnology Unit, Ente per le Nuove Tecnologie, l'Energia e l'Ambiente, CR-Casaccia, Rome, Italy
2 Department of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, Rome, Italy
3 Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy

To whom correspondence should be addressed: Anna Saran, Biotechnology Unit, ENEA CR-Casaccia, Via Anguillarese 301, 00123 Rome, Italy. E-mail: saran{at}casaccia.enea.it, Phone: +39 06 30484304, Fax: +39 06 30483644

Patched1 heterozygous mice (Ptch1+/-) are useful for basal cell carcinoma (BCC) studies, being remarkably susceptible to BCC induction by UV 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 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 ER{alpha}, down-regulation of ERβ, and upregulation of cyclin D1 in papillomas from ovariectomized Car-S relative to papillomas from CN females. Thus, an imbalanced ER{alpha}/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.

Key Words: Patched • Car-S • BCC • SCC • radiation

4 These authors contributed equally in this work

Received July 16, 2008; revised September 15, 2008; accepted October 19, 2008.


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M. Mancuso, D. Gallo, and A. Saran
Re: Modulation of basal and squamous cell carcinoma by endogenous estrogen in mouse models of skin cancer
Carcinogenesis, April 1, 2009; 30(4): 721 - 721.
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