Glutamate enrichment as new diagnostic opportunity in breast cancer

Jan Budczies, Berit M. Pfitzner, Balazs Györffy, Klaus Jürgen Winzer, Cornelia Radke, Manfred Dietel, Oliver Fiehn, Carsten Denkert

Research output: Contribution to journalArticle

48 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1619-1628
Number of pages10
JournalInternational Journal of Cancer
Volume136
Issue number7
DOIs
StatePublished - Apr 1 2015

Fingerprint

Glutamine
Glutamic Acid
Breast Neoplasms
Metabolomics
Glutaminase
Neoplasms
Breast
Peroxisome Proliferator-Activated Receptors
Gas Chromatography
Cluster Analysis
Mass Spectrometry
Multivariate Analysis
Biomarkers
Genome
RNA
Gene Expression
Survival

Keywords

  • Breast cancer
  • Glutamate
  • Glutamine
  • Metabolomics
  • PPAR signaling

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Budczies, J., Pfitzner, B. M., Györffy, B., Winzer, K. J., Radke, C., Dietel, M., ... Denkert, C. (2015). Glutamate enrichment as new diagnostic opportunity in breast cancer. International Journal of Cancer, 136(7), 1619-1628. https://doi.org/10.1002/ijc.29152

Glutamate enrichment as new diagnostic opportunity in breast cancer. / Budczies, Jan; Pfitzner, Berit M.; Györffy, Balazs; Winzer, Klaus Jürgen; Radke, Cornelia; Dietel, Manfred; Fiehn, Oliver; Denkert, Carsten.

In: International Journal of Cancer, Vol. 136, No. 7, 01.04.2015, p. 1619-1628.

Research output: Contribution to journalArticle

Budczies, J, Pfitzner, BM, Györffy, B, Winzer, KJ, Radke, C, Dietel, M, Fiehn, O & Denkert, C 2015, 'Glutamate enrichment as new diagnostic opportunity in breast cancer', International Journal of Cancer, vol. 136, no. 7, pp. 1619-1628. https://doi.org/10.1002/ijc.29152
Budczies J, Pfitzner BM, Györffy B, Winzer KJ, Radke C, Dietel M et al. Glutamate enrichment as new diagnostic opportunity in breast cancer. International Journal of Cancer. 2015 Apr 1;136(7):1619-1628. https://doi.org/10.1002/ijc.29152
Budczies, Jan ; Pfitzner, Berit M. ; Györffy, Balazs ; Winzer, Klaus Jürgen ; Radke, Cornelia ; Dietel, Manfred ; Fiehn, Oliver ; Denkert, Carsten. / Glutamate enrichment as new diagnostic opportunity in breast cancer. In: International Journal of Cancer. 2015 ; Vol. 136, No. 7. pp. 1619-1628.
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