Glucocorticoid receptor activation signals through forkhead transcription factor 3a in breast cancer cells

Wei Wu, Min Zou, Deanna R. Brickley, Travis Pew, Suzanne D. Conzen

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Activation of the glucocorticoid receptor (GR) plays a critical role in the stress response of virtually all cell types. Despite recent advances in large-scale genomic and proteomic data acquisition, identification of physiologically relevant molecular events downstream of nuclear hormone receptor activation remains challenging. By analyzing gene expression changes 30 min after dexamethasone (Dex) treatment, we previously found that immediate induction of serum and glucocorticoid-regulated kinase-1 (SGK-1) expression is required for GR-mediated mammary epithelial cell survival signaling. We now report that activation of the GR mediates Forkhead transcription factor 3a (FOXO3a) phosphorylation and inactivation in mammary epithelial cells. GR-mediated induction of SGK-1 expression is required for FOXO3a inactivation; additional growth factor stimulation is not required. To further explore the gene expression changes that occur downstream of GR-mediated FOXO3a inactivation, we analyzed temporal gene expression data and selected GR-down-regulated genes containing core FOXO3a binding motifs in their proximal promoters. This approach revealed several previously unrecognized transcriptional target genes of FOXO3a, including IGF binding protein-3 (IGFBP-3). Endogenous IGFBP-3 expression was confirmed to be dependent on the GR-SGK-1-FOXO3a signaling pathway. Moreover, GR activation decreased FOXO3a-induced apoptosis in SK-BR-3 breast cancer cells. Collectively, our data suggest that GR-mediated FOXO3a inactivation is an important mechanism contributing to glucocorticoid-mediated mammary epithelial cell survival.

Original languageEnglish (US)
Pages (from-to)2304-2314
Number of pages11
JournalMolecular Endocrinology
Volume20
Issue number10
DOIs
StatePublished - Oct 9 2006
Externally publishedYes

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Forkhead Transcription Factors
Glucocorticoid Receptors
Breast Neoplasms
Insulin-Like Growth Factor Binding Protein 3
Breast
Epithelial Cells
Gene Expression
Cell Survival
Cytoplasmic and Nuclear Receptors
Proteomics
Dexamethasone
Glucocorticoids
Genes
Intercellular Signaling Peptides and Proteins
Phosphorylation
Apoptosis

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Glucocorticoid receptor activation signals through forkhead transcription factor 3a in breast cancer cells. / Wu, Wei; Zou, Min; Brickley, Deanna R.; Pew, Travis; Conzen, Suzanne D.

In: Molecular Endocrinology, Vol. 20, No. 10, 09.10.2006, p. 2304-2314.

Research output: Contribution to journalArticle

Wu, Wei ; Zou, Min ; Brickley, Deanna R. ; Pew, Travis ; Conzen, Suzanne D. / Glucocorticoid receptor activation signals through forkhead transcription factor 3a in breast cancer cells. In: Molecular Endocrinology. 2006 ; Vol. 20, No. 10. pp. 2304-2314.
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