Stage Analysis of Breast Cancer Metabolomics: A System Biology Approach.

BACKGROUND: Breast cancer (BC) is the most common malignancy in women worldwide. Altered miRNA profile can disturb the metabolic homeostatic via regulation of gene expression in BC.

METHODS: In the present study to evaluate which miRNA, regulate metabolic pathways according to their stage, we performed comprehensive analysis of BC expression (mRNA and miRNA) of a set of patients by comparing samples of solid tumor tissue and adjacent tissue. The mRNA and miRNA data of breast cancer were downloaded from the cancer genome database (TCGA) using TCGAbiolinks package. Differentially expressed (mRNAs and miRNAs) was determined by DESeq2 package and predict valid miRNA-mRNA pairs using multiMiR package. All analyses were performed using the R software.  Compound-reaction-enzyme-gene network was constructed using the Metscape a plugin for Cytoscape software. Then, core subnetwork computed by CentiScaPe, another plugin for Cytoscape.

RESULTS: In Stage I, hsa-miR-592, hsa-miR-449a and hsa-miR-1269a targeted HS3ST4, ACSL1 and USP9Y genes respectively. In stage II, hsa-miR-3662, Hsa-miR-429, and hsa-miR-1269a targeted GYS2, HAS3, ASPA, TRHDE, USP44, GDA, DGAT2, and USP9Y genes. In stage III, hsa-miR-3662 targeted TRHDE, GYS2, DPYS, HAS3, NMNAT2, ASPA genes. In stage IV, hsa-miR-429, has-miR-23c, and hsa-miR-449a targeted genes GDA, DGAT2, PDK4, ALDH1A2, ENPP2, and KL. Those miRNAs and their targets were identified as the discriminative elements for the four stages of breast cancer.

CONCLUSION: The most notable differences between BC and normal tissue in four stages  involved multiple pathways and metabolites include: carbohydrate metabolism (e.g., Amylose, N-acetyl-D-glucosamin, beta-D-Glucuronoside, ""g""-CEHC-glucuronide, ""a""-CEHC-glucuronide, Heparan-glucosamine, 5,6-Dihydrouracil, 5,6-Dihydrothymine), branch-chain amino acid metabolism (e.g., N-Acetyl-L-aspartate, N-Formyl-L-aspartate, N`-acetyl-L-asparagine), Retinal metabolism (e.g., Retinal, 9-`cis`-retinal, 13-`cis`-retinal) and (FAD, NAD) as central coenzymes of metabolism. Set of crucial microRNAs and targeted genes plus the related metabolites were introduced for four stages of BC that can be consider for therapeutic and diagnostic purposes in the different stages of disease.