title: Glutamate enrichment as new diagnostic opportunity in breast cancer.
abstract: Exogenous glutamine is an important source of energy and molecular building blocks for many tumors. There is a renewed interest in therapeutically targeting glutamine metabolism due to the recent discovery of two novel glutaminase inhibitors. To quantify the dysregulation of the glutamate-glutamine equilibrium in breast cancer, metabolomics analysis of 270 clinical breast cancer samples and 97 normal breast samples was carried out using gas chromatography combined with time-of-flight mass spectrometry. Positive correlation between glutamate and glutamine in normal breast tissues switched to negative correlation between glutamate and glutamine in breast cancer tissues. Compared with the ratio of glutamate to glutamine in normal tissues, we found 56% of the ER+ tumor tissues and 88% of the ER- tumor tissues glutamate-enriched. The glutamate-to-glutamine ratio (GGR) significantly correlated with ER status (p = 8.0E-09) and with tumor grade (p = 3.3E-05). Higher levels of GGR were associated with prolonged overall survival in univariate analysis (HR = 0.77, p = 0.027) and in multivariate analysis (HR = 0.73, p = 0.038). GGR levels were reflected in an unsupervised clustering of metabolomics profiles. In a supervised analysis of metabolomics data and of genome-wide expression data, replacement of GGR by metabolite surrogate markers was feasible, while replacement of GGR by RNA markers had a limited accuracy. Functional analysis of the gene expression data showed negative correlation between glutamate enrichment and activation of peroxisome proliferator-activated receptor (PPAR) pathway. Our findings may have important implications for patient stratification related to utilization of glutaminase inhibitors.
authors.affiliation: Institute of Pathology, Charité University Hospital, Berlin, Germany; German Cancer Consortium (DKTK), partner site Berlin, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.forename: Berit M
authors.initials: BM
authors.lastname: Pfitzner
authors.forename: Balazs
authors.initials: B
authors.lastname: Györffy
authors.forename: Klaus-Jürgen
authors.initials: KJ
authors.lastname: Winzer
authors.forename: Cornelia
authors.initials: C
authors.lastname: Radke
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
mesh_terms: D015415:Biomarkers; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D055432:Metabolomics; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D047492:Peroxisome Proliferator-Activated Receptors; D011960:Receptors, Estrogen; D005973:Glutamine; D018698:Glutamic Acid
keywords: PPAR signaling; breast cancer; glutamate; glutamine; metabolomics