Metabolomic Profiling Reveals Increased Arginine Metabolism in ER- Breast Cancers from African-American Women
Ashwini K Esnakula, Tammey J Naab, Luisel J Ricks-Santi, Wayne AI Frederick, Robert L DeWitty, Jr., Yasmine Kanaan. Howard University Hospital, Washington, DC; Howard University College of Medicine, Washington, DC
Background: Estrogen receptor negative (ER-) breast cancer, which is associated with chemotherapy resistance and poorer survival, is more common in younger African-American women. The various genetic and epigenetic differences between ER - and ER+ breast cancers have been studied, but only rare studies have analyzed the dysregulated metabolic pathways between these two subtypes. Metabolomics, a study of cellular small-molecule metabolites, is used to analyze the metabolic differences between ER+ and ER- tumors. The goal of our study is to establish the metabolomic profile of biochemicals in various amino acid pathways in ER- and ER+ breast cancers from African-American women.
Design: Breast cancer tumor tissue methanol extracts from 15 ER- and 15 ER+ African-American women were analyzed using liquid/gas-chromatography coupled to mass spectrometry. Following log transformation and imputation with minimal observed values for each compound, Welch's two-sample t-test was used to identify metabolites that differed significantly between experimental groups. Statistical significance was assumed if P ≤ 0.05.
Results: Global biochemical reveal significant differences in amino acid metabolism in ER+ and ER- tumors. The most significant difference was observed in arginine metabolism. ER- tumors showed significant increase in arginine when compared to ER- tumors. Various metabolites of arginine metabolism, including citrulline, putrescine and proline, were significantly increased in ER- tumors. Citrulline, an intermediate in the production of nitric oxide from arginine, was increased by 16.2 fold in ER- tumors. Nitric oxide mediates inflammatory signaling and vascular tone in tumors. ER- tumors also showed 15.1 fold increase in putrescine, indicating proliferative signaling via this polyamine. Arginine metabolites associated with extracellular matrix remodeling were also increased in ER- samples, including proline, 4-hydroxyproline and proline-hydroxy-proline.
Conclusions: Our study indicates robust utilization of arginine in ER- tumors which is correlated with increased metabolites linked to nitric oxide-mediated inflammatory signaling, cell proliferation, energy metabolism and extracellular matrix remodeling. This increase in arginine uptake and metabolism might be a potential influence on the aggressiveness of ER- tumors when compared to ER+ tumors.
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 14, Tuesday Morning