title: TP53 mutation hits energy metabolism and increases glycolysis in breast cancer.
abstract: Promising new hallmarks of cancer is alteration of energy metabolism that involves molecular mechanisms shifting cancer cells to aerobe glycolysis. Our goal was to evaluate the correlation between mutation in the commonly mutated tumor suppressor gene TP53 and metabolism. We established a database comprising mutation and RNA-seq expression data of the TCGA repository and performed receiver operating characteristics (ROC) analysis to compare expression of each gene between TP53 mutated and wild type samples. All together 762 breast cancer samples were evaluated of which 215 had TP53 mutation. Top up-regulated metabolic genes include glycolytic enzymes (e.g. HK3, GPI, GAPDH, PGK1, ENO1), glycolysis regulator (PDK1) and pentose phosphate pathway enzymes (PGD, TKT, RPIA). Gluconeogenesis enzymes (G6PC3, FBP1) were down-regulated. Oxygen consumption and extracellular acidification rates were measured in TP53 wild type and mutant breast cell lines with a microfluorimetric analyzer. Applying metabolic inhibitors in the presence and absence of D-glucose and L-glutamine in cell culture experiments resulted in higher glycolytic and mitochondrial activity in TP53 mutant breast cancer cell lines. In summary, TP53 mutation influences energy metabolism at multiple levels. Our results provide evidence for the synergistic activation of multiple hallmarks linking to these the mutation status of a key driver gene.
authors: MTA TTK Lendület Cancer Biomarker Research Group, H-1117, Budapest, Hungary.
authors: Hajnalka
authors: H
authors: Harami-Papp
authors: MTA TTK Lendület Cancer Biomarker Research Group, H-1117, Budapest, Hungary.|Semmelweis University, 2nd Department of Pediatrics, H-1094, Budapest, Hungary.
authors: Lőrinc S
authors: LS
authors: Pongor
authors: MTA TTK Lendület Cancer Biomarker Research Group, H-1117, Budapest, Hungary.
authors: Gyöngyi
authors: G
authors: Munkácsy
authors: Semmelweis University, Department of Medical Biochemistry, H-1094, Budapest, Hungary.
authors: Gergő
authors: G
authors: Horváth
authors: Semmelweis University, Department of Medical Biochemistry, H-1094, Budapest, Hungary.
authors: Ádám M
authors: ÁM
authors: Nagy
authors: Semmelweis University, Department of Medical Biochemistry, H-1094, Budapest, Hungary.
authors: Attila
authors: A
authors: Ambrus
authors: Semmelweis University, 2nd Department of Pediatrics, H-1094, Budapest, Hungary.
authors: Péter
authors: P
authors: Hauser
authors: Semmelweis University, 2nd Department of Pediatrics, H-1094, Budapest, Hungary.
authors: András
authors: A
authors: Szabó
authors: Semmelweis University, Department of Medical Biochemistry, H-1094, Budapest, Hungary.
authors: László
authors: L
authors: Tretter
authors: MTA TTK Lendület Cancer Biomarker Research Group, H-1117, Budapest, Hungary.
authors: Balázs
authors: B
authors: Győrffy
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D006801:Humans; D009154:Mutation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: Warburg effect; breast cancer; glycolytic efficiency; next generation sequencing