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Updated: Oct 6, 2025

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 15, 2013

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Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids

Gido Snaterse1, Rosinda Mies1, Wytske M van Weerden2

  • 1Department of Internal Medicine, Section of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

Prostate Cancer and Prostatic Diseases
|January 20, 2022
PubMed
Abstract

Insights

Androgen receptor (AR) mutations in castration-resistant prostate cancer (CRPC) can alter hormone sensitivity. This study identifies key mutations and their response to various steroids, offering insights into AR pathway reactivation and potential treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Androgen receptor (AR) ligand-binding domain (LBD) mutations are found in approximately 20% of castration-resistant prostate cancer (CRPC) patients.
  • These mutations can lead to promiscuous ligand binding, but their affinity for various steroid hormone intermediates remains largely uncharacterized.
  • Understanding these interactions is crucial for elucidating AR pathway reactivation mechanisms in CRPC.

Approach:

  • A meta-analysis identified prevalent AR-LBD mutations (ARL702H, ARH875Y, ART878A) in CRPC patients.
  • Luciferase reporter and quantitative fluorescent microscopy assays were employed to screen AR mutants for sensitivity to endogenous steroids and synthetic glucocorticoids.
  • The study investigated the stimulation of wild-type AR (ARWT) and mutant ARs by testosterone, 11-ketotestosterone (11KT), cortisol, prednisolone, and dexamethasone.

Key Points:

  • Testosterone and 11KT exhibit subnanomolar affinity for ARWT.
  • The ARH875Y mutation significantly enhances sensitivity to 11KT, while ARL702H shows markedly reduced sensitivity to 11KT.
  • Cortisol and prednisolone stimulate ARL702H, but dexamethasone does not, suggesting its potential as an alternative therapeutic in specific cases.

Conclusions:

  • Testosterone and 11KT are key activators of ARWT, with 11KT being a more potent activator of ARH875Y.
  • Dexamethasone may serve as a viable alternative to prednisolone for patients with the ARL702H mutation.
  • These findings provide critical insights into AR-mediated signaling in CRPC and inform potential therapeutic strategies.

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