NMR-based metabolomic analysis identifies RON-DEK-β-catenin dependent metabolic pathways and a gene signature that stratifies breast cancer patient survival

Abstract

Background Advances in detection techniques and treatment have increased the diagnosis of breast cancer at early stages; however, recurrence occurs in all breast cancer subtypes, and both recurrent and de novo metastasis are typically treatment resistant. A growing body of evidence supports the notion that metabolic plasticity drives cancer recurrence. RON and DEK are proteins that promote cancer metastasis and synergize mechanistically to activate β-catenin, but the metabolic consequences are unknown. Methods To ascertain RON-DEK-β-catenin dependent metabolic pathways, we utilized an NMR-based metabolomics approach to determine steady state levels of metabolites. We also interrogated altered metabolic pathway gene expression for prognostic capacity in breast cancer patient relapse-free and distant metastasis-free survival and discover a metabolic signature that is likely associated with recurrence. Results RON-DEK-β-catenin loss showed a consistent metabolite regulation of succinate and phosphocreatine. Consistent metabolite alterations between RON and DEK loss (but not β-catenin) were found in media glucose consumption, lactate secretion, acetate secretion, and intracellular glutamine and glutathione levels. Consistent metabolite alterations between RON and β-catenin loss (and not DEK) were found only in intracellular lactate levels. Further pathway hits include β-catenin include glycolysis, glycosylation, TCA cycle/anaplerosis, NAD+ production, and creatine dynamics. Genes in these pathways epistatic to RON-DEK-β-catenin were used to define a gene signature that prognosticates breast cancer patient survival and response to chemotherapy. Conclusions The RON-DEK-β-catenin axis regulates the numerous metabolic pathways with significant associations to breast cancer patient outcomes.

A Pilot Study on Biochemical Profile of Follicular Fluid in Breast Cancer Patients

“…Detecting cancer by metabolic profiling of biofluids facilitates easy and minimally invasive diagnostics, and allows for screening [ 21 ]. Metabolomics has been widely utilized in BC field [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ] using different type of samples (i.e., blood plasma/serum, saliva, tissues, urine, and cells).…”