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Abstract
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.
Highlights
Breast cancer is the most frequently diagnosed, and second deadliest cancer in women, with more than 200,000 new patients, and approximately 40,000 estimated deaths per year only in the UnitedStates [1]
We propose that the mechanism by which cholesterol may exert its effects on ER+ and triple negative breast cancer (TNBC) cells involves cholesterol binding to ERRα and changing its conformation, thereby enhancing ERRα interaction with its coactivator PGC-1α, with the increased ERRα-PGC-1α interaction resulting in augmented expression of ERRα itself and of its target genes implicated in cellular metabolism, including isocitrate dehydrogenase 3A (IDH3A), pyruvate dehydrogenase kinase 4 (PDK4), superoxide dismutase 2 (SOD2), glutathione S-transferase M1 (GSTM1) and vascular endothelial growth factor (VEGF)
We demonstrate that cholesterol binds ERRα, enhances its interaction with its transcriptional co-activator PGC-1α and promotes ERRα transcriptional activity in ER-positive and in triple-negative breast cancer cells
Summary
Breast cancer is the most frequently diagnosed, and second deadliest cancer in women, with more than 200,000 new patients, and approximately 40,000 estimated deaths per year only in the UnitedStates [1]. It is necessary to reduce incidence and improve outcome by therapeutic approaches addressing known breast cancer risk factors. Dyslipidemia and high dietary cholesterol intake are critical risk factors for breast cancer in pre- and post-menopausal women [2]. Post-menopausal women with high dietary cholesterol intake have been reported to have a ~50% increase in the risk of breast cancer [2,7]. In several different mouse models of breast cancer, high dietary cholesterol alone resulted in a significant decrease in tumor latency, and an increase in tumor volume and total tumor burden [8,9,10,11,12]. It was shown that established breast cancer is associated with
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