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Carcinogenesis Advance Access originally published online on October 24, 2008
Carcinogenesis 2009 30(2):340-347; 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. Mancuso{dagger}, D. Gallo1,{dagger}, S. Leonardi, M. Pierdomenico, E. Pasquali2, I. De Stefano1, S. Rebessi, M. Tanori, G. Scambia1, V. Di Majo, V. Covelli, S. Pazzaglia and A. Saran*

Biotechnology Unit, Ente per le Nuove Tecnologie, l'Energia e l'Ambiente, CR-Casaccia, Via Anguillarese 301, 00123 Rome, Italy
1 Department of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, Rome 00198, Italy
2 Department of Experimental Oncology, Istituto Nazionale Tumori, Milan 20133, Italy

* To whom correspondence should be addressed. Tel: +39 06 30484304; Fax: +39 06 30483644; Email: saran{at}casaccia.enea.it

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)-{alpha}, downregulation 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.

Abbreviations: BCC, basal cell carcinoma; CN, control; Car-S, carcinogenesis susceptible; DMBA, 9,10-dimethyl-1,2-benzanthracene; ER, estrogen receptor; NMSC, non-melanoma skin cancer; OVX, ovariectomized; PTCH, patched; SCC, squamous cell carcinoma; SHH, Sonic Hedgehog; TPA, 12-O-tetradecanoyl-phorbol-13-acetate; UV, ultraviolet

{dagger} These authors contributed equally to 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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