Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis

Irina V. Budunova, Dariusz Kowalczyk, Paloma Pérez, Ya Juan Yao, José L. Jorcano, Thomas J. Slaga

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3279-3287
Number of pages9
JournalOncogene
Volume22
Issue number21
DOIs
StatePublished - May 22 2003
Externally publishedYes

Keywords

  • Glucocorticoid receptor
  • NF-κB
  • Skin carcinogenesis
  • Transgenic mice

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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