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

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

Interrogating Causal Effects of Body Composition and Puberty‐Related Risk Factors on Adolescent Idiopathic Scoliosis: A Two‐Sample Mendelian Randomization Study

ABSTRACT Adolescent idiopathic scoliosis (AIS) is the most common form of pediatric musculoskeletal disorder. Observational studies have pointed to several risk factors for AIS, but almost no evidence exists to support their causal association with AIS. Here, we applied Mendelian randomization (MR), known to limit bias from confounding and reverse causation, to investigate causal associations between body composition and puberty‐related exposures and AIS risk in Europeans and Asians. For our two‐sample MR studies, we used single nucleotide polymorphisms (SNPs) associated with body mass index (BMI), waist‐hip ratio, lean mass, childhood obesity, bone mineral density (BMD), 25‐hydroxyvitamin D (25OHD), age at menarche, and pubertal growth in large European genome‐wide association studies (GWAS), and with adult osteoporosis risk and age of menarche in Biobank Japan. We extracted estimates of the aforementioned SNPs on AIS risk from the European or Asian subsets of the largest multiancestry AIS GWAS (N = 7956 cases/88,459 controls). The results of our inverse variance‐weighted (IVW) MR estimates suggest no causal association between the aforementioned risk factors and risk of AIS. Pleiotropy‐sensitive MR methods yielded similar results. However, restricting our analysis to European females with AIS, we observed a causal association between estimated BMD and the risk of AIS (IVW odds ratio for AIS = 0.1, 95% confidence interval 0.01 to 0.7, p = 0.02 per SD increase in estimated BMD), but this association was no longer significant after adjusting for BMI, body fat mass, and 25OHD and remained significant after adjusting for age at menarche in multivariable MR. In conclusion, we demonstrated a protective causal effect of BMD on AIS risk in females of European ancestry, but this effect was modified by BMI, body fat mass, and 25OHD levels. Future MR studies using larger AIS GWAS are needed to investigate small effects of the aforementioned exposures on AIS. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research