Metabolomic Profiling Reveals Upregulated Fatty Acid Metabolism in Ductal Breast Cancers from African-American Women

Abstract

Background: Ductal breast cancers (BCa), especially aggressive high grade triple negative breast cancers are more common in younger African-American patients when compared to other ethnic groups. Metabolomics, a study of cellular small-molecule metabolites, is undertaken. The goal is to identify metabolite markers in energy pathways that separate breast cancers from benign breast disease in African-American women. Design: We used untargeted 1H NMR metabolomics to identify common and unique metabolite markers in fibrocystic disease, fibroadenomas and breast cancer specimens. Fresh frozen tissues from 48 patients with median age of 21-78 years were analyzed by untargeted metabolomics analysis using 1H nuclear magnetic resonance (NMR) spectroscopy. Multivariate and statistical analyses were used to determine the most significant metabolites that would differentiate the different BCa stages and grades from control mammoplasty tissues. Results: In breast cancer patient samples, significant elevations of key fatty acid metabolism pathway markers including carnitine, choline, O-phosphocholine, O-acetylcholine and sn-Glycero-3-Phosphocholine are found when compared to fibrocystic disease and fibroadenoma (p<0.05). Conclusions: Our study shows upregulated fatty acid metabolic pathway in all grades of ductal breast cancers when compared to benign breast changes and fibroadenoma. Carnitine transports long chain acyl fatty acids from cytoplasm to mitochondria that undergo beta fatty acid oxidation generating acetyl CoA that provides ATP via Krebs cycle. Phosphocholine and sn-Glycero-3-Phosphocholine are intermediates in lipid metabolism. Choline undergoes oxidation to trimethylglycine that acts as coenzyme in homocysteine-methionine pathway, ultimately affecting methylation of DNA. Our studies indicate fatty acid metabolism intermediates are involved in the development and progression of ductal breast cancers. Inhibiting fatty acid metabolism may be useful for treatment of ductal breast cancers.