A master regulator of cholesterol biosynthesis constitutes a therapeutic liability of triple negative breast cancer

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Demin Cai1, Xiong Zhang1, Hong-Wu Chen1

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

Molecular & Cellular Oncology
|March 12, 2020
PubMed

Insights

Triple-negative breast cancers reprogram cholesterol metabolism using the master regulator RORγ. This finding reveals vulnerabilities exploitable by RORγ inhibitors and statins for TNBC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Lipid and cholesterol reprogramming are hallmarks of certain cancer subtypes.
  • Estrogen receptor-positive (ER+) breast cancers exhibit distinct metabolic profiles compared to other subtypes.

Purpose of the Study:

  • To investigate the role of nuclear receptor RAR-related orphan receptor γ (RORγ) in cholesterol biosynthesis in triple-negative breast cancers (TNBCs).
  • To determine if RORγ acts as a master regulator of cholesterol metabolism in TNBCs.
  • To explore therapeutic strategies targeting RORγ in TNBC.

Main Methods:

  • Analysis of gene expression and metabolic pathways in TNBC and ER+ breast cancer models.
  • Investigation of the regulatory role of RORγ in cholesterol biosynthesis.
  • Evaluation of the efficacy of RORγ inhibitors and statins in preclinical TNBC models.

Main Results:

  • TNBCs, unlike ER+ breast cancers, utilize RORγ as the primary activator of cholesterol biosynthesis.
  • RORγ plays a dominant role in regulating cholesterol metabolism, surpassing sterol regulatory element-binding protein 2 (SREBP2).
  • TNBCs demonstrate significant sensitivity to RORγ inhibitors and combination therapy with statins.

Conclusions:

  • RORγ is a critical driver of cholesterol biosynthesis in TNBC.
  • Targeting RORγ presents a promising therapeutic strategy for TNBC.
  • Combination therapy involving RORγ inhibitors and statins may enhance treatment efficacy for TNBC.
Keywords:
ER-positive breast cancerRORγSREBP2TNBCcholesterol homeostasischromatinstatinstherapy

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