Cholesterol-Induced Metabolic Reprogramming in Breast Cancer Cells Is Mediated via the ERRα Pathway

SIMPLE SUMMARY: There is increasing evidence that obesity and high circulating cholesterol levels are associated with an increased risk of recurrence and a higher mortality rate in breast cancer patients via altering the metabolic programming in breast cancer cells. However, the underlying molecular mechanism by which high cholesterol levels reprogram the metabolic pathways in breast cancer cells is not well-understood. We have previously demonstrated that cholesterol acts as an endogenous agonist of estrogen-related receptor α (ERRα), a strong regulator of cellular metabolism. The aim of the current study is to demonstrate whether cholesterol/obesity mediates its pathogenic effect in breast cancer cells via altering metabolic pathways in an ERRα-dependent manner. The findings of this study provide mechanistic insights into the link between cholesterol/obesity and metabolic reprogramming in breast cancer patients and reveal the metabolic vulnerabilities in such breast cancer patients that could be therapeutically targeted. ABSTRACT: The molecular mechanism underlying the metabolic reprogramming associated with obesity and high blood cholesterol levels is poorly understood. We previously reported that cholesterol is an endogenous ligand of the estrogen-related receptor alpha (ERRα). Using functional assays, metabolomics, and genomics, here we show that exogenous cholesterol alters the metabolic pathways in estrogen receptor-positive (ER+) and triple-negative breast cancer (TNBC) cells, and that this involves increased oxidative phosphorylation (OXPHOS) and TCA cycle intermediate levels. In addition, cholesterol augments aerobic glycolysis in TNBC cells although it remains unaltered in ER+ cells. Interestingly, cholesterol does not alter the metabolite levels of glutaminolysis, one-carbon metabolism, or the pentose phosphate pathway, but increases the NADPH levels and cellular proliferation, in both cell types. Importantly, we show that the above cholesterol-induced modulations of the metabolic pathways in breast cancer cells are mediated via ERRα. Furthermore, analysis of the ERRα metabolic gene signature of basal-like breast tumours of overweight/obese versus lean patients, using the GEO database, shows that obesity may modulate ERRα gene signature in a manner consistent with our in vitro findings with exogenous cholesterol. Given the close link between high cholesterol levels and obesity, our findings provide a mechanistic explanation for the association between cholesterol/obesity and metabolic reprogramming in breast cancer patients.