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RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype

Demin Cai1, Junjian Wang1, Bei Gao2

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

Nature Communications
|October 13, 2019
PubMed

Insights

Triple-negative breast cancer (TNBC) utilizes a cholesterol synthesis pathway regulated by RORγ. Inhibiting RORγ effectively reduces tumor growth, offering a new therapeutic strategy for TNBC.

Area of Science:

  • Molecular biology
  • Oncology
  • Metabolic pathways

Background:

  • Metabolic reprogramming is crucial for tumor growth.
  • Triple-negative breast cancer (TNBC) has distinct metabolic vulnerabilities compared to other subtypes.
  • Identifying subtype-specific metabolic targets is key for effective cancer therapy.

Purpose of the Study:

  • To investigate the role of cholesterol biosynthesis in TNBC.
  • To identify key regulators of the cholesterol pathway in TNBC.
  • To evaluate RORγ as a potential therapeutic target for TNBC.

Main Methods:

  • Comparative analysis of cholesterol biosynthesis in TNBC versus estrogen receptor-positive breast cancer.
  • Genetic and pharmacological inhibition of RORγ.
  • Assessment of RORγ's interaction with SREBP2 and chromatin acetylation.
  • Tumor regression studies in patient-derived xenografts and immune-intact models.
  • Combination therapy with statins.

Main Results:

  • TNBC exhibits a hyper-activated cholesterol biosynthesis program linked to RORγ.
  • RORγ is a master regulator of cholesterol biosynthesis, activating genes and recruiting SREBP2.
  • RORγ inhibition reduces tumor cholesterol and causes tumor regression.
  • Combination of RORγ antagonists and statins shows synergistic anti-tumor effects in TNBC models.

Conclusions:

  • RORγ is a critical regulator of cholesterol biosynthesis and a potential therapeutic target in TNBC.
  • Targeting RORγ offers a promising strategy for TNBC treatment.
  • Combined inhibition of RORγ and cholesterol synthesis via statins demonstrates significant anti-tumor synergy in TNBC.

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