Physical activity, metabolites, and breast cancer associations

Background The effects of habitual physical activity on physiology and disease prevention are not fully understood. We examined the associations between physical activity, metabolites in systemic circulation, and breast cancer risk. Methods Total physical activity levels were assessed using doubly labeled water, accelerometers, and previous day recalls in the IDATA study (N=707 participants, ages 50-74 years, 51% women). Assessments occurred 1-6 times over a 12-month period and blood samples were collected twice. Partial Spearman correlations were used to estimate associations between physical activity and 843 serum metabolites, corrected for multiple testing using the false discovery rate (p-adj<0.05). Associations between physical activity-associated metabolites and breast cancer were explored in a prospective cohort (621 cases, 621 controls) using conditional logistic regression. Results Physical activity was associated with 164 metabolites, spanning a wide range of pathways, including many amino acid pathways, glucose homeostasis, and bile acid metabolism. Nine physical activity-associated metabolites were also associated with postmenopausal breast cancer risk. Key metabolites were N-acetylthreonine, isovalerylglycine, 2-methylbutyroylcarnitine (amino acids and derivatives), androsteroid monosulfate C19H28O6S (1), and X-21310. These metabolites were consistent with a protective role of physical activity on breast cancer prevention and particularly implicated a role for branched chain amino acid catabolism. Sphingomyelin (d18:1/20:1, d18:2/20:0) levels were lower in participants with higher physical activity energy expenditure and were also associated with lower breast cancer risk. Conclusion Physical activity is associated with a broad range of metabolites, some of which are also associated with reduced breast cancer risk, highlighting potential metabolic pathways for cancer prevention.