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Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding
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Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor

Yong Zhang1, Donald Y M Leung, Steven K Nordeen

  • 1Department of Pediatrics, National Jewish Health, Denver, Colorado 80206, USA.

The Journal of Biological Chemistry
|July 10, 2009
PubMed

Insights

Estrogen hinders glucocorticoid effectiveness in breast cancer cells by reducing glucocorticoid receptor (GR) activity. Inhibiting protein phosphatase 5 (PP5) restores glucocorticoid sensitivity, suggesting a new therapeutic target.

Area of Science:

  • Molecular Endocrinology
  • Cancer Biology
  • Cell Signaling

Background:

  • Glucocorticoids suppress cell proliferation but have limited efficacy in breast cancer treatment.
  • Estrogen's influence on glucocorticoid action and inflammatory diseases suggests potential cross-talk.
  • The molecular mechanisms underlying estrogen-glucocorticoid interactions remain largely unknown.

Purpose of the Study:

  • To investigate the molecular mechanisms of cross-talk between estrogen and glucocorticoid signaling in breast cancer cells.
  • To determine how estrogen affects glucocorticoid receptor (GR) activity and gene induction.
  • To explore the role of protein phosphatase 5 (PP5) in mediating these interactions.

Main Methods:

  • Utilized MCF-7 and T47D breast cancer cell lines.
  • Assessed glucocorticoid-induced gene expression (MKP-1, SGK) and GR phosphorylation (Ser-211).
  • Employed gene knockdown techniques for protein phosphatase 5 (PP5) and analyzed effects on GR activity and cell proliferation.

Main Results:

  • Estrogen inhibited glucocorticoid induction of MKP-1 and SGK genes in breast cancer cells.
  • Estrogen reduced GR phosphorylation at Ser-211, a marker of GR activity, without affecting nuclear translocation.
  • Estrogen increased PP5 expression, which dephosphorylates GR at Ser-211; PP5 knockdown restored GR activity and glucocorticoid-mediated suppression of estrogen-promoted proliferation.

Conclusions:

  • Estrogen-induced PP5 mediates cross-talk by dephosphorylating and inactivating the glucocorticoid receptor (GR).
  • PP5 inhibition can antagonize estrogen-promoted cell proliferation, restoring glucocorticoid sensitivity.
  • Targeting PP5 may offer a strategy to enhance corticosteroid therapy efficacy in estrogen-responsive breast cancers.

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