Abstract
Simple SummaryThere 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.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.
Highlights
Obesity and elevated blood cholesterol levels are associated with an increased risk and poor prognosis in breast cancer patients, and this has been linked to profound metabolic alterations that promote tumour growth, progression, and/or response to therapy [1,2]
In line with the high cholesterol-induced ERRα-dependent metabolic alterations demonstrated in vitro, we found that obesity may modulate ERRα metabolic target gene expression in breast cancer patients, detected by analysis of the Gene Expression Omnibus (GEO) database
When ERRα was inhibited using cpd29, Cancers 2021, 13, 2605 the enhancing effect of exogenous cholesterol on triple-negative breast cancer (TNBC)-PDX cell proliferation was compromised, with no significant difference between cells treated with both cholesterol and cpd29 when compared to cells treated with cpd29 alone
Summary
Obesity and elevated blood cholesterol levels are associated with an increased risk and poor prognosis in breast cancer patients, and this has been linked to profound metabolic alterations that promote tumour growth, progression, and/or response to therapy [1,2]. Growing evidence shows that many cancer cells, compared to normal cells, mainly rely on glucose metabolism, using aerobic glycolysis, a process known as the Warburg effect [7]. Even though in this process, ATP generation is less efficient than oxidative phosphorylation (OXPHOS), it invests the carbon skeletons of glucose in several biosynthetic pathways necessary to generate the required molecular building blocks for cell proliferation [7]. The metabolic alterations that cancer cells adopt are responsive to their environment and as such, glycolysis is often favored in solid breast tumours that experience bouts of hypoxia, and mitochondrial OXPHOS levels can remain active even at low oxygen levels [11,12]. It has been demonstrated that breast cancer progression is associated with increased reliance on OXPHOS, as this can favor survival of circulating tumour cells, and promote site-directed metastasis, and resistance to chemotherapy and targeted therapeutics [15,16,17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
