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Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis

Oncogene volume 22, pages 3279–3287 (2003)Cite this article

Abstract

Glucocorticoids are effective inhibitors of epidermal proliferation and skin tumorigenesis. Glucocorticoids affect cellular functions via glucocorticoid receptor (GR), a well-known transcription factor. Recently, we generated skin-targeted transgenic mice overexpressing GR under control of the keratin5 promoter (K5-GR mice). To test the hypothesis that GR plays a role as a tumor suppressor in skin, we bred K5-GR transgenic mice with Tg.AC transgenic mice, which express v-Ha-ras oncogene in the skin, and compared the susceptibility of F1 offspring to TPA-induced skin carcinogenesis. GR overexpression in the epidermis dramatically inhibited skin tumor development. In K5-GR/ras+ double transgenic mice papillomas developed later and the average number of tumors per animal was 15% (in males) and 40% (in females) of the number seen in wild type (w.t./ras+) littermates. In addition, the papillomas in w.t./ras+ animals were eight to nine times larger. GR overexpression resulted in a decrease in keratinocyte proliferation combined with a modest increase in apoptosis and differentiation of keratinocytes in K5-GR/ras+ papillomas. Our data clearly indicate that interference of GR transgenic protein with nuclear factor kappa B (NF-κB) transcription factor had resulted in NF-κB blockage in K5-GR/ras+ tumors. We discuss the role of NF-κB blockage in tumor-suppressor effect of GR.

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Abbreviations

B6D2:

F1 C57B1 × DBA mice

BrdU:

bromodeoxyuridine

CDK:

cyclin-dependent kinase

DMBA:

7,12-dimethylbenz[a]-anthracene

GR:

glucocorticoid receptor

GRE:

glucocorticoid response element

IκB:

inhibitory proteins of NF-κB

Mt1:

metallothionein 1

NF-κB:

nuclear factor kappa B

TPA:

12-O-tetradecanoyl-phorbol-13-acetate

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Acknowledgements

We thank Dr R Cannon for his generous gift of reagents, technical support and valuable comments, Dr R Strange for his critical suggestions and P Wolfe for statistical analysis of data. We acknowledge Dr C Conti and Dr A Bravo for their help with histopathological diagnosis of tumors. This study was supported by NIH grant RO1-CA-79065-01 and partially by grant SAF2002-04368-C02-01 from the Spanish Ministry of Science and Technology.

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Author notes

  1. Irina V Budunova and Dariusz Kowalczyk: These authors contributed equally to the work

  2. Dariusz Kowalczyk: Department of Cell Biology, The Maria Sklodowska Memorial Cancer Center, W.K. Roentgen 5, 02-781 Warsaw, Poland

Authors and Affiliations

  1. AMC Cancer Research Center, 1600 Pierce Street, Denver, 80214, CO, USA

    Irina V Budunova, Dariusz Kowalczyk, Ya Juan Yao & Thomas J Slaga

  2. Institute of Biomedicine of Valencia, CSIC, Valencia, E-46010, Spain

    Paloma Pérez

  3. Project on Cell and Molecular Biology and Gene Therapy, CIEMAT, Madrid, E-28040, Spain

    José L Jorcano

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  1. Irina V Budunova
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Correspondence to Irina V Budunova.

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Budunova, I., Kowalczyk, D., Pérez, P. et al. Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis. Oncogene 22, 3279–3287 (2003). https://doi.org/10.1038/sj.onc.1206383

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