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Mutations at the boundary of the hinge and ligand binding domain of the androgen receptor confer increased

G Buchanan1, M Yang, J M Harris

  • 1Flinders Cancer Centre, Flinders University and Flinders Medical Centre Adelaide SA 5042, Australia.

Molecular Endocrinology (Baltimore, Md.)
|January 6, 2001
PubMed

Insights

New androgen receptor (AR) gene mutations in prostate cancer increase receptor activity. These AR variants may drive hormone-refractory disease by altering protein interactions.

Area of Science:

  • Molecular biology
  • Cancer research
  • Endocrinology

Background:

  • The androgen receptor (AR) is a nuclear transcription factor crucial for androgen signaling.
  • AR plays a vital role in various target tissues, including prostate cancer.
  • Dysregulation of AR signaling is implicated in the progression of prostate cancer.

Purpose of the Study:

  • To identify and characterize novel mutations in the androgen receptor (AR) gene associated with prostate cancer.
  • To investigate the functional consequences of these AR mutations on receptor activity and ligand binding.
  • To explore the potential role of AR variants in the development of hormone-refractory prostate cancer.

Main Methods:

  • Analysis of AR gene mutations in human prostate cancer samples and a mouse model.
  • Functional assays to assess AR variant activity in response to various ligands and antagonists.
  • Homology modeling to predict structural changes and their impact on protein interactions.

Main Results:

  • Identified AR gene mutations at residues (668)QPIF(671) in both human prostate cancer and a mouse model.
  • Mutated AR variants exhibited 2- to 4-fold increased activity compared to wild-type AR.
  • Increased activity was observed across multiple ligands, including androgens and hydroxyflutamide, without affecting receptor levels or binding kinetics.
  • Homology modeling suggested decreased hydrophobicity at a protein-protein interaction surface, implying altered interactions.

Conclusions:

  • Naturally occurring AR gene mutations can lead to hyperactive receptors.
  • These hyperactive AR variants may contribute to the emergence of hormone-refractory prostate cancer.
  • Altered protein-protein interactions, driven by decreased surface hydrophobicity, likely mediate the enhanced activity of AR variants.

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