Comparative metabolomics of estrogen receptor positive and estrogen receptor negative breast cancer: alterations in glutamine and beta-alanine metabolism

Budczies, Jan; Brockmöller, Scarlet; Müller, Berit; Barupal, Dinesh Kumar; Richter-Ehrenstein, Christiane; Kleine-Tebbe, A.; Griffin, Julian L.; Orešič, Matej; Dietel, Manfred; Denkert, Carsten; Fiehn, Oliver

doi:10.1016/j.jprot.2013.10.002

Cited by 154 publications

(167 citation statements)

References 34 publications

Supporting

Mentioning

152

Contrasting

Unclassified

Order By: Relevance

“…The experimental design included predefined splitting of the tissues in training set (TS, 2/3 of tumors) and a validation set (VS, 1/3 of tumors) having similar clinicopathological characteristics, for details see Ref. 25.…”

Section: Study Cohortmentioning

confidence: 99%

See 1 more Smart Citation

Glutamate enrichment as new diagnostic opportunity in breast cancer

Budczies

Pfitzner

Győrffy

et al. 2014

Intl Journal of Cancer

Self Cite

110

View full text Add to dashboard Cite

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 ER1 tumor tissues and 88% of the ER2 tumor tissues glutamate-enriched. The glutamateto-glutamine ratio (GGR) significantly correlated with ER status (p 5 8.0E-09) and with tumor grade (p 5 3.3E-05). Higher levels of GGR were associated with prolonged overall survival in univariate analysis (HR 5 0.77, p 5 0.027) and in multivariate analysis (HR 5 0.73, p 5 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.Altered energy metabolism is acknowledged as one of the emerging hallmarks of cancer. 1 Recently, there is a renewed interest in the metabolic transformation occurring in cancer cells and in targeting metabolic enzymes for cancer therapy. 2-4 However, the discovery of dysregulated metabolism in tumors dates back to the work of Otto Warburg in the 1920s. Warburg observed that cancer cells exhibit elevated glycolysis and that much of the generated pyruvate is fermented to lactate rather than feed to the TCA cycle and used for oxidative phosphorylation. 5,6 This phenomenon occurs under anaerobic and even under aerobic conditions ("aerobic glycolysis").A second change that occurs in central metabolism of many cancer cells is the alteration of glutamine metabolism. 7-9 Glutamine can be used to replenish the TCA cycle instead of glucose and feed in carbon and nitrogen for synthesis of nucleotides, several amino acids and glutathione. Further, glutamine can be used for energy production and in transformed cultured cells glutamine driven oxidative phosphorylation was recently shown to be the main source of

show abstract

Section: Study Cohortmentioning

confidence: 99%

“…In two preceding studies, we analyzed the metabolite changes between breast cancer tissues and normal breast tissues 24 and between ER2 breast cancer and ER1 breast cancer 25 on the -omics scale. After discovery of promising new glutaminase inhibitors, it would be desirable to identify those cancer patients that are most likely to profit from the new agents.…”

mentioning

confidence: 99%

Glutamate enrichment as new diagnostic opportunity in breast cancer

Budczies

Pfitzner

Győrffy

et al. 2014

Intl Journal of Cancer

Self Cite

110

View full text Add to dashboard Cite

show abstract

“…Cancer metabolism has also been shown to modify the chromatin of cells, the tumor microenvironment, or antitumor immunity (5). We and others reported that metabolite patterns of breast tumors are greatly different from those in the adjacent noncancerous tissue and vary between disease subtypes (6)(7)(8). A key discovery from these studies was the observation that 2-hydroxy glutarate (2HG) can accumulate in breast tumors (7,8).…”

Section: Introductionmentioning

confidence: 99%

ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming

Mishra

Tang

Putluri

et al. 2017

Journal of Clinical Investigation

View full text Add to dashboard Cite

“…47 A further study by the same group revealed that beta-alanine could distinguish between ER+ and ER-breast cancer. 48 The most commonly applied 'omics approaches and the latest methods/technologies used in each of these are summarised below and in Table 1.…”

Section: Metabolomicsmentioning

confidence: 99%

Application of omic technologies in cancer research

et al. 2018

View full text Add to dashboard Cite

Understanding the biology of health and diseases such as cancer, generating insight into the triggers and potentiators of disease and the development of therapeutic approaches to counter and treat disease requires detailed interrogation of inherited genes, and the dynamic positioning of the transcriptome and proteome. In the last 10 years, significant technological developments and increases in sample throughput capabilities have led to a dramatic increase in the size and complexity of the datasets that can be generated. A key challenge now is to develop robust approaches for analysing and interpreting these, and converting data into biologically-and clinically-relevant information. Herein, we provide an overview of approaches for acquiring, integrating and interpreting complex datasets generated using multiple omic platforms, with a focus on the field of cancer research, and highlight key successful data handling and integration applications.

show abstract

Comparative metabolomics of estrogen receptor positive and estrogen receptor negative breast cancer: alterations in glutamine and beta-alanine metabolism

Cited by 154 publications

References 34 publications

Glutamate enrichment as new diagnostic opportunity in breast cancer

Glutamate enrichment as new diagnostic opportunity in breast cancer

ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming

Application of omic technologies in cancer research

Contact Info

Product

Resources

About