A joint analysis of metabolomics and genetics of breast cancer

Abstract

IntroductionRemodeling of cellular metabolism appears to be a consequence and possibly a cause of oncogenic transformation in human cancers. Specific aspects of altered tumor metabolism may be amenable to therapeutic intervention and could be coordinated with other targeted therapies. In breast cancer, the genetic landscape has been defined most comprehensively in efforts such as The Cancer Genome Atlas (TCGA). However, little is known about how alterations of tumor metabolism correlate with this landscape.MethodsIn total 25 cancers (23 fully analyzed by TCGA) and 5 normal breast specimens were analyzed by gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry, quantitating 399 identifiable metabolites.ResultsWe found strong differences correlated with hormone receptor status with 18% of the metabolites elevated in estrogen receptor negative (ER-) cancers compared to estrogen receptor positive (ER+) including many glycolytic and glycogenolytic intermediates consistent with increased Warburg effects. Glutathione (GSH) pathway components were also elevated in ER- tumors consistent with an increased requirement for handling higher levels of oxidative stress. Additionally, ER- tumors had high levels of the oncometabolite 2-hydroxyglutarate (2-HG) and the immunomodulatory tryptophan metabolite kynurenine. Kynurenine levels were correlated with the expression of tryptophan-degrading enzyme (IDO1). However, high levels of 2-HG were not associated with somatic mutations or expression levels of IDH1 or IDH2. BRCA1 mRNA levels were positively associated with coenzyme A, acetyl coenzyme A, and GSH and negatively associated with multiple lipid species, supporting the regulation of ACC1 and NRF2 by BRCA1. Different driver mutations were associated with distinct patterns of specific metabolites, such as lower levels of several lipid-glycerophosphocholines in tumors with mutated TP53. A strong metabolomic signature associated with proliferation rate was also observed; the metabolites in this signature overlap broadly with metabolites that define ER status as receptor status and proliferation rate were correlated.ConclusionsThe addition of metabolomic profiles to the public domain TCGA dataset provides an important new tool for discovery and hypothesis testing of the genetic regulation of tumor metabolism. Particular sets of metabolites may reveal insights into the metabolic dysregulation that underlie the heterogeneity of breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0415-9) contains supplementary material, which is available to authorized users.

ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming

“…Additional information for the experiments with [1][2][3][4][5][6][7][8][9][10][11][12][13] C]glutamine can be found in the Supplemental Methods. To determine the flux of [ 13 C]glutamine into succinate and citrate in presence and absence of cell-permeant 2HG, MCF12A cells were seeded in a 6-well plate and serum-starved overnight before being exposed to either 1 mM octyl-2HG or control compound (PAMO) in RPMI medium containing 2 mM [1-5 13 C]glutamine (Cambridge Isotope Laboratories).…”

“…We and others previously reported that total 2HG accumulates in a subset of human breast tumors that were primarily estrogen receptor-negative (ER-negative) (7,8). Here, we interrogated the enantiomeric forms of 2HG in 15 ER-negative human breast tumors using enantiomer-specific targeted mass spectrometry ( Figure 1A).…”

“…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). These tumors did not harbor the isocitrate dehydrogenase 1 and 2 (IDH1 and -2) mutations that have previously been linked to 2HG accumulation in gliomas and leukemia (9,10), indicating that an alternative mechanism must lead to increased 2HG in breast cancer.…”

“…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).…”

Estrogen Receptor α Promotes Breast Cancer by Reprogramming Choline Metabolism

“…Individuals with ERα positive (ERα+) breast cancer as determined by immunohistochemistry (IHC), accounts for approximately 70% of breast cancer patients. Comparative metabolomics profiling of ERα+ and ERα negative (ERα-) breast cancer indicated clear metabolic differences correlated to hormone receptor status, including differences in glutamine and beta-alanine metabolism, as well as phospholipid metabolism (9)(10)(11). Furthermore, estrogen stimulation enhanced the rate of glucose consumption, lactate production (aerobic glycolysis), and glutamate synthesis, and decreased the level of phosphocholine (PCho) in breast cancer cell lines (12-14).…”