Abstract B82: Metabolomic analysis reveals association between leucine and lipogenesis for the formation of lipid rafts in the membrane of primary breast tumor samples

Abstract

Abstract Introduction: Upregulation of lipogenesis, via FASN, represents a nearly-universal phenotypic alteration in most malignancies. Experimental studies indicated that leucine deprivation decreased expression of lipogenic gene FASN, saturated fatty acid (SFA) synthesis, and induced apoptosis in breast cancer cells. However, the association between lipogenesis and leucine is not well understood in breast cancer. Methods: In this sense, metabolomics analysis was performed from primary breast cancer and adjacent tissue samples from cohort of 96 breast cancer patients from the Institut Gustave-Roussy and Institute Curie – Paris, University of Debrecen – Hungary, and University of Tartu – Estonia. The Biocrates Life Science® company performed the metabolomics analysis using the Absolute IDQ p180 kit. Statistical analysis was performed by MetaboAnalyst 3.0 software (p <0.05). We performed the combined analysis of genes from public database (GEO) with genes of interest related to metabolic pathways. Differently expressed genes analyses between breast tumor and normal breast tissue were performed by TMev program using TestT student (p< 0.05). We selected only differently expressed genes related with leucine metabolism and lipogenesis for further analyses. Results: Indeed, in the tumor tissue we observed an increase of lipogenesis, and BCAA (branched chain amino acid) uptake and catabolism. The amino acids valine and isoleucine were used for the synthesis of succinyl and alpha ketoglutarate to meet the increased demand for the TCA (tricarboxylic acid) cycle. Surprisingly, the leucine metabolites indicated that it was used for cholesterol synthesis. Moreover, in tumor tissue samples an increase of SFA synthesis was observed, such as palmitic acid, sphingolipids, and phosphatidylcolines SFA enriched. Together with increased synthesis of cholesterol (via leucine), these data suggest an increase of lipid rafts in the breast tumor cells membrane when compared to normal breast adjacent tissue. To validate these data, we found 12 genes differently expressed genes related to leucine/cholesterol/lipogenesis/lipid rafts from public database. Conclusion: Our results indicate that lipogenic phenotype is associated with leucine metabolism to promote survival and proliferation, through lipid rafts increase, necessary to receptors (i.e., HER2, EGFR) location and activation within the breast tumor cells membrane. Citation Format: Jéssica Reis, Ismael Dale, Angela Logullo, Maria Mitzi, Dan Waitzberg, Graziela Ravacci. Metabolomic analysis reveals association between leucine and lipogenesis for the formation of lipid rafts in the membrane of primary breast tumor samples [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B82.