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Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding
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Biochemical characterization of nuclear receptors for vitamin D3 and glucocorticoids in prostate stroma cell

Alejandro A Hidalgo1, Viviana P Montecinos, Roberto Paredes

  • 1Laboratory of Molecular Endocrinology, Department of Physiopathology, University of Concepcion, Concepcion, Chile.

Biochemical and Biophysical Research Communications
|July 19, 2011
PubMed

Insights

Prostate cancer stroma alters vitamin D receptor (VDR) and glucocorticoid receptor (GR) function, potentially causing hormone resistance. This disruption in coactivator recruitment impacts treatment strategies for advanced prostate cancer.

Area of Science:

  • Endocrinology
  • Oncology
  • Molecular Biology

Background:

  • Prostate cancer can become resistant to androgen therapies.
  • 1α,25-Dihydroxyvitamin D(3) (1,25D(3)) and glucocorticoids are potential treatments for advanced prostate cancer.
  • Stromal cell signals in the prostate microenvironment influence cancer development and hormone independence.

Purpose of the Study:

  • To investigate the function of the vitamin D receptor (VDR) and glucocorticoid receptor (GR) in prostate stromal fibroblasts.
  • To compare VDR and GR activity in benign (BAS) versus carcinoma-associated stroma (CAS).
  • To understand how stromal changes contribute to hormone resistance in prostate cancer.

Main Methods:

  • Isolation of fibroblasts from human benign and carcinoma-associated prostate stroma.
  • Assessment of VDR-mediated transcriptional activity using a CYP24-luciferase reporter assay.
  • Analysis of VDR and GR function via expression of modified receptors and coactivator recruitment using chromatin immunoprecipitation (ChIP).

Main Results:

  • VDR-mediated transcriptional activity was reduced in most CAS samples compared to BAS.
  • Restoring VDR expression partially recovered activity in some CAS, suggesting receptor alterations.
  • GR-mediated transcriptional activity was also altered in CAS.
  • ChIP assays showed decreased coactivator SRC-1/CBP recruitment to the CYP24 promoter in CAS.

Conclusions:

  • Alterations in VDR and GR function within the prostate tumor microenvironment contribute to hormone resistance.
  • Disrupted coactivator recruitment (SRC-1/CBP) is implicated in promoting hormone resistance in prostate cancer.
  • These findings emphasize the importance of molecular diagnostics and targeted drug design for the tumor microenvironment.

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