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Open AccessArticle

Cholesterol as an Endogenous Ligand of ERRα Promotes ERRα-Mediated Cellular Proliferation and Metabolic Target Gene Expression in Breast Cancer Cells

1
Division of Plastic Surgery, Department of Surgery, Faculty of Medicine, McGill University, Montreal, QC H3G 1A4, Canada
2
Department of Biochemistry and Molecular Medicine, Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC H3C 1J7, Canada
*
Author to whom correspondence should be addressed.
Cells 2020, 9(8), 1765; https://doi.org/10.3390/cells9081765
Received: 10 May 2020 / Revised: 26 June 2020 / Accepted: 15 July 2020 / Published: 23 July 2020
Breast cancer is the 2nd leading cause of cancer-related death among women. Increased risk of breast cancer has been associated with high dietary cholesterol intake. However, the underlying mechanisms are not known. The nuclear receptor, estrogen-related receptor alpha (ERRα), plays an important role in breast cancer cell metabolism, and its overexpression has been linked to poor survival. Here we identified cholesterol as an endogenous ligand of ERRα by purification from human pregnancy serum using a GST-ERRα affinity column and liquid chromatography-tandem mass spectrometry (LC-MS/MS). We show that cholesterol interacts with ERRα and induces its transcriptional activity in estrogen receptor positive (ER+) and triple negative breast cancer (TNBC) cells. In addition, we show that cholesterol enhances ERRα-PGC-1α interaction, induces ERRα expression itself, augments several metabolic target genes of ERRα, and increases cell proliferation and migration in both ER+ and TNBC cells. Furthermore, the stimulatory effect of cholesterol on metabolic gene expression, cell proliferation, and migration requires the ERRα pathway. These findings provide a mechanistic explanation for the increased breast cancer risk associated with high dietary cholesterol and possibly the pro-survival effect of statins in breast cancer patients, highlighting the clinical relevance of lowering cholesterol levels in breast cancer patients overexpressing ERRα. View Full-Text
Keywords: breast cancer; cholesterol; estrogen related receptor α; statins; human pregnancy serum breast cancer; cholesterol; estrogen related receptor α; statins; human pregnancy serum
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MDPI and ACS Style

Ghanbari, F.; Mader, S.; Philip, A. Cholesterol as an Endogenous Ligand of ERRα Promotes ERRα-Mediated Cellular Proliferation and Metabolic Target Gene Expression in Breast Cancer Cells. Cells 2020, 9, 1765. https://doi.org/10.3390/cells9081765

AMA Style

Ghanbari F, Mader S, Philip A. Cholesterol as an Endogenous Ligand of ERRα Promotes ERRα-Mediated Cellular Proliferation and Metabolic Target Gene Expression in Breast Cancer Cells. Cells. 2020; 9(8):1765. https://doi.org/10.3390/cells9081765

Chicago/Turabian Style

Ghanbari, Faegheh; Mader, Sylvie; Philip, Anie. 2020. "Cholesterol as an Endogenous Ligand of ERRα Promotes ERRα-Mediated Cellular Proliferation and Metabolic Target Gene Expression in Breast Cancer Cells" Cells 9, no. 8: 1765. https://doi.org/10.3390/cells9081765

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