Altered glucocorticoid receptor expression and function during mouse skin carcinogenesis

Irina V. Budunova, Steve Carbajal, Ho Il Kang, Aurora Viaje, Thomas J Slaga

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Clucocorticoids are the most potent inhibitors of tumor promotion in mouse skin, when applied with a promoting agent at the early stages of promotion. However, established skin papillomas become resistant to growth inhibition by glucocorticoids. Glucocorticoid control of cellular functions is mediated by the glucocorticoid receptor (GR), a well-known transcription factor. Here we present data on GR expression and function in mouse papillomas and squamous cell carcinomas. Tumors were produced in SENCAR mice by a 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate two-stage protocol. In early papillomas (after 15-20 wk of promotion), northern blotting revealed a decrease in the GR mRNA level that was confirmed by a binding assay. However, in late papillomas (after 30-40 wk of promotion), and especially in squamous cell carcinomas, the level of GR in both assays was similar to or higher than the GR level in normal epidermis. To test the functional capability of GR in tumors, we compared the effect of the synthetic glucocorticoid fluocinolone acetonide (FA) on keratinocyte proliferation and on expression of glucocorticoid-responsive genes in normal epidermis, hyperplastic skin surrounding tumors, and mouse skin papillomas. FA strongly inhibited DNA synthesis in keratinocytes in normal skin and tumor-surrounding skin but had no effect on DNA synthesis in papillomas. In addition, FA strongly induced metallothionein 1 expression and inhibited connexin 26 expression in skin but did not affect expression of these genes in tumors. These data suggest that alteration of both the expression and function of GR may be an important mechanism of tumor promotion in skin.

Original languageEnglish (US)
Pages (from-to)177-185
Number of pages9
JournalMolecular Carcinogenesis
Volume18
Issue number3
DOIs
StatePublished - Mar 1997
Externally publishedYes

Fingerprint

Glucocorticoid Receptors
Carcinogenesis
Papilloma
Skin
Fluocinolone Acetonide
Glucocorticoids
Neoplasms
Keratinocytes
Epidermis
Squamous Cell Carcinoma
Inbred SENCAR Mouse
Metallothionein
DNA
Tetradecanoylphorbol Acetate
Northern Blotting
Transcription Factors
Gene Expression
Messenger RNA
Growth
Genes

Keywords

  • Glucocorticoid receptor
  • Proliferation
  • Skin tumors

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

Altered glucocorticoid receptor expression and function during mouse skin carcinogenesis. / Budunova, Irina V.; Carbajal, Steve; Kang, Ho Il; Viaje, Aurora; Slaga, Thomas J.

In: Molecular Carcinogenesis, Vol. 18, No. 3, 03.1997, p. 177-185.

Research output: Contribution to journalArticle

Budunova, Irina V. ; Carbajal, Steve ; Kang, Ho Il ; Viaje, Aurora ; Slaga, Thomas J. / Altered glucocorticoid receptor expression and function during mouse skin carcinogenesis. In: Molecular Carcinogenesis. 1997 ; Vol. 18, No. 3. pp. 177-185.
@article{ba5b65fadfe94e8499c17396df68bfe1,
title = "Altered glucocorticoid receptor expression and function during mouse skin carcinogenesis",
abstract = "Clucocorticoids are the most potent inhibitors of tumor promotion in mouse skin, when applied with a promoting agent at the early stages of promotion. However, established skin papillomas become resistant to growth inhibition by glucocorticoids. Glucocorticoid control of cellular functions is mediated by the glucocorticoid receptor (GR), a well-known transcription factor. Here we present data on GR expression and function in mouse papillomas and squamous cell carcinomas. Tumors were produced in SENCAR mice by a 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate two-stage protocol. In early papillomas (after 15-20 wk of promotion), northern blotting revealed a decrease in the GR mRNA level that was confirmed by a binding assay. However, in late papillomas (after 30-40 wk of promotion), and especially in squamous cell carcinomas, the level of GR in both assays was similar to or higher than the GR level in normal epidermis. To test the functional capability of GR in tumors, we compared the effect of the synthetic glucocorticoid fluocinolone acetonide (FA) on keratinocyte proliferation and on expression of glucocorticoid-responsive genes in normal epidermis, hyperplastic skin surrounding tumors, and mouse skin papillomas. FA strongly inhibited DNA synthesis in keratinocytes in normal skin and tumor-surrounding skin but had no effect on DNA synthesis in papillomas. In addition, FA strongly induced metallothionein 1 expression and inhibited connexin 26 expression in skin but did not affect expression of these genes in tumors. These data suggest that alteration of both the expression and function of GR may be an important mechanism of tumor promotion in skin.",
keywords = "Glucocorticoid receptor, Proliferation, Skin tumors",
author = "Budunova, {Irina V.} and Steve Carbajal and Kang, {Ho Il} and Aurora Viaje and Slaga, {Thomas J}",
year = "1997",
month = "3",
doi = "10.1002/(SICI)1098-2744(199703)18:3<177::AID-MC7>3.0.CO;2-C",
language = "English (US)",
volume = "18",
pages = "177--185",
journal = "Molecular Carcinogenesis",
issn = "0899-1987",
publisher = "Wiley-Liss Inc.",
number = "3",

}

TY - JOUR

T1 - Altered glucocorticoid receptor expression and function during mouse skin carcinogenesis

AU - Budunova, Irina V.

AU - Carbajal, Steve

AU - Kang, Ho Il

AU - Viaje, Aurora

AU - Slaga, Thomas J

PY - 1997/3

Y1 - 1997/3

N2 - Clucocorticoids are the most potent inhibitors of tumor promotion in mouse skin, when applied with a promoting agent at the early stages of promotion. However, established skin papillomas become resistant to growth inhibition by glucocorticoids. Glucocorticoid control of cellular functions is mediated by the glucocorticoid receptor (GR), a well-known transcription factor. Here we present data on GR expression and function in mouse papillomas and squamous cell carcinomas. Tumors were produced in SENCAR mice by a 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate two-stage protocol. In early papillomas (after 15-20 wk of promotion), northern blotting revealed a decrease in the GR mRNA level that was confirmed by a binding assay. However, in late papillomas (after 30-40 wk of promotion), and especially in squamous cell carcinomas, the level of GR in both assays was similar to or higher than the GR level in normal epidermis. To test the functional capability of GR in tumors, we compared the effect of the synthetic glucocorticoid fluocinolone acetonide (FA) on keratinocyte proliferation and on expression of glucocorticoid-responsive genes in normal epidermis, hyperplastic skin surrounding tumors, and mouse skin papillomas. FA strongly inhibited DNA synthesis in keratinocytes in normal skin and tumor-surrounding skin but had no effect on DNA synthesis in papillomas. In addition, FA strongly induced metallothionein 1 expression and inhibited connexin 26 expression in skin but did not affect expression of these genes in tumors. These data suggest that alteration of both the expression and function of GR may be an important mechanism of tumor promotion in skin.

AB - Clucocorticoids are the most potent inhibitors of tumor promotion in mouse skin, when applied with a promoting agent at the early stages of promotion. However, established skin papillomas become resistant to growth inhibition by glucocorticoids. Glucocorticoid control of cellular functions is mediated by the glucocorticoid receptor (GR), a well-known transcription factor. Here we present data on GR expression and function in mouse papillomas and squamous cell carcinomas. Tumors were produced in SENCAR mice by a 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate two-stage protocol. In early papillomas (after 15-20 wk of promotion), northern blotting revealed a decrease in the GR mRNA level that was confirmed by a binding assay. However, in late papillomas (after 30-40 wk of promotion), and especially in squamous cell carcinomas, the level of GR in both assays was similar to or higher than the GR level in normal epidermis. To test the functional capability of GR in tumors, we compared the effect of the synthetic glucocorticoid fluocinolone acetonide (FA) on keratinocyte proliferation and on expression of glucocorticoid-responsive genes in normal epidermis, hyperplastic skin surrounding tumors, and mouse skin papillomas. FA strongly inhibited DNA synthesis in keratinocytes in normal skin and tumor-surrounding skin but had no effect on DNA synthesis in papillomas. In addition, FA strongly induced metallothionein 1 expression and inhibited connexin 26 expression in skin but did not affect expression of these genes in tumors. These data suggest that alteration of both the expression and function of GR may be an important mechanism of tumor promotion in skin.

KW - Glucocorticoid receptor

KW - Proliferation

KW - Skin tumors

UR - http://www.scopus.com/inward/record.url?scp=0030935823&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030935823&partnerID=8YFLogxK

U2 - 10.1002/(SICI)1098-2744(199703)18:3<177::AID-MC7>3.0.CO;2-C

DO - 10.1002/(SICI)1098-2744(199703)18:3<177::AID-MC7>3.0.CO;2-C

M3 - Article

C2 - 9115588

AN - SCOPUS:0030935823

VL - 18

SP - 177

EP - 185

JO - Molecular Carcinogenesis

JF - Molecular Carcinogenesis

SN - 0899-1987

IS - 3

ER -