Prioritization of metabolic genes as novel therapeutic targets in estrogen-receptor negative breast tumors using multi-omics data and text mining

Abstract

Estrogen-receptor negative (ERneg) breast cancer is an aggressive breast cancer subtype in the need for new therapeutic options. We have analyzed metabolomics, proteomics and transcriptomics data for a cohort of 276 breast tumors (MetaCancer study) and nine public transcriptomics datasets using univariate statistics, meta-analysis, Reactome pathway analysis, biochemical network mapping and text mining of metabolic genes. In the MetaCancer cohort, a total of 29% metabolites, 21% proteins and 33% transcripts were significantly different (raw p <0.05) between ERneg and ERpos breast tumors. In the nine public transcriptomics datasets, on average 23% of all genes were significantly different (raw p <0.05). Specifically, up to 60% of the metabolic genes were significantly different (meta-analysis raw p <0.05) across the transcriptomics datasets. Reactome pathway analysis of all omics showed that energy metabolism, and biosynthesis of nucleotides, amino acids, and lipids were associated with ERneg status. Text mining revealed that several significant metabolic genes and enzymes have been rarely reported to date, including PFKP, GART, PLOD1, ASS1, NUDT12, FAR1, PDE7A, FAHD1, ITPK1, SORD, HACD3, CDS2 and PDSS1. Metabolic processes associated with ERneg tumors were identified by multi-omics integration analysis of metabolomics, proteomics and transcriptomics data. Overall results suggested that TCA anaplerosis, proline biosynthesis, synthesis of complex lipids and mechanisms for recycling substrates were activated in ERneg tumors. Under-reported genes were revealed by text mining which may serve as novel candidates for drug targets in cancer therapies. The workflow presented here can also be used for other tumor types.