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Updated: Mar 23, 2026

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

Published on: March 6, 2018

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ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer

Junjian Wang1, June X Zou1, Xiaoqian Xue2

  • 1Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.

Nature Medicine
|March 29, 2016
PubMed

Insights

Retinoic acid receptor-related orphan receptor gamma (ROR-γ) drives androgen receptor (AR) expression in castration-resistant prostate cancer (CRPC). ROR-γ antagonists suppress tumor growth and sensitize CRPC to enzalutamide, offering a new therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Androgen receptor (AR) is overexpressed and hyperactivated in castration-resistant prostate cancer (CRPC).
  • The molecular drivers of AR overexpression in CRPC remain poorly understood.

Purpose of the Study:

  • To investigate the role of retinoic acid receptor-related orphan receptor gamma (ROR-γ) in driving AR expression in CRPC.
  • To evaluate ROR-γ antagonists as a potential therapeutic strategy for advanced prostate cancer.

Main Methods:

  • Analysis of ROR-γ expression and amplification in metastatic CRPC tumors.
  • Investigating ROR-γ's mechanism in recruiting coactivators (NCOA1/SRC-1, NCOA3/SRC-3) to the AR-ROR response element (RORE).
  • Assessing the effects of ROR-γ antagonists on AR and AR-V7 expression, AR binding, H3K27ac, and AR target gene network in cell lines and xenograft models.

Main Results:

  • ROR-γ is overexpressed and amplified in metastatic CRPC tumors.
  • ROR-γ directly drives AR gene transcription by recruiting coactivators to the AR-RORE.
  • ROR-γ antagonists reduce AR and AR-V7 expression, diminish AR binding and H3K27ac, and suppress AR target gene network.
  • ROR-γ antagonists inhibit tumor growth in AR-expressing xenografts and sensitize CRPC to enzalutamide without toxicity.

Conclusions:

  • ROR-γ acts upstream of AR, playing a critical role in CRPC progression.
  • Targeting ROR-γ represents a promising therapeutic strategy for advanced prostate cancer, particularly in combination with enzalutamide.

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