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Metabolomics of oncogene-specific metabolic reprogramming during breast cancer.

ABSTRACT: Background:The complex yet interrelated connections between cancer metabolism and oncogenic driver genes are relatively unexplored but have the potential to identify novel biomarkers and drug targets with prognostic and therapeutic value. The goal of this study was to identify global metabolic profiles of breast tumors isolated from multiple transgenic mouse models and to identify unique metabolic signatures driven by these oncogenes. Methods:Using mass spectrometry (GC-MS, LC-MS/MS, and capillary zone electrophoresis (CZE)-MS platforms), we quantified and compared the levels of 374 metabolites in breast tissue from normal and transgenic mouse breast cancer models overexpressing a panel of oncogenes (PyMT, PyMT-DB, Wnt1, Neu, and C3-TAg). We also compared the mouse metabolomics data to published human metabolomics data already linked to clinical data. Results:Through analysis of our metabolomics data, we identified metabolic differences between normal and tumor breast tissues as well as metabolic differences unique to each initiating oncogene. We also quantified the metabolic profiles of the mammary fat pad versus mammary epithelium by CZE-MS/MS. However, the differences between the tissues did not account for the majority of the metabolic differences between the normal mammary gland and breast tumor tissues. Therefore, the differences between the cohorts were unlikely due to cellular heterogeneity. Of the mouse models used in this study, C3-TAg was the only cohort with a tumor metabolic signature composed of ten metabolites that had significant prognostic value in breast cancer patients. Gene expression analysis identified candidate genes that may contribute to the metabolic reprogramming. Conclusions:This study identifies oncogene-induced metabolic reprogramming within mouse breast tumors and compares the results to that of human breast tumors, providing a unique look at the relationship between and clinical value of oncogene initiation and metabolism during breast cancer.

SUBMITTER: Dai C

PROVIDER: S-EPMC5881178 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Metabolomics of oncogene-specific metabolic reprogramming during breast cancer.

Dai Chen C Arceo Jennifer J Arnold James J Sreekumar Arun A Dovichi Norman J NJ Li Jun J Littlepage Laurie E LE

Cancer & metabolism 20180403

<h4>Background</h4>The complex yet interrelated connections between cancer metabolism and oncogenic driver genes are relatively unexplored but have the potential to identify novel biomarkers and drug targets with prognostic and therapeutic value. The goal of this study was to identify global metabolic profiles of breast tumors isolated from multiple transgenic mouse models and to identify unique metabolic signatures driven by these oncogenes.<h4>Methods</h4>Using mass spectrometry (GC-MS, LC-MS/ ...[more]

PMID: 29619217

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Project description:Kidney cancer, or renal cell carcinoma (RCC), is a disease of increasing incidence that commonly is seen in the general practice of nephrology. Despite this state of affairs, this fascinating and highly morbid disease frequently is under-represented, or even absent, from the curriculum of nephrologists in training and generally is underemphasized in national nephrology meetings, both scientific as well as clinical. Although classic concepts in cancer research in general had led to the concept that cancer is a disease resulting from mutations in the control of growth-regulating pathways, reinforced by the discovery of oncogenes, more contemporary research, particularly in kidney cancer, has uncovered changes in metabolic pathways mediated by those same genes that control tumor energetics and biosynthesis. This adaptation of classic biochemical pathways to the tumor's advantage has been labeled metabolic reprogramming. For example, in the case of kidney cancer there exists a near-universal presence of von Hippel-Lindau tumor suppressor (pVHL) inactivation in the most common form, clear cell RCC (ccRCC), leading to activation of hypoxia-relevant and other metabolic pathways. Studies of this and other pathways in clear cell RCC (ccRCC) have been particularly revealing, leading to the concept that ccRCC can itself be considered a metabolic disease. For this reason, the relatively new method of metabolomics has become a useful technique in the study of ccRCC to tease out those pathways that have been reprogrammed by the tumor to its maximum survival advantage. Furthermore, identification of the nodes of such pathways can lead to novel areas for drug intervention in a disease for which such targets are seriously lacking. Further research and dissemination of these concepts, likely using omics techniques, will lead to clinical trials of therapeutics specifically targeted to tumor metabolism, rather than those generally toxic to all proliferating cells. Such novel agents are highly likely to be more effective than existing drugs and to have far fewer adverse effects. This review provides a general overview of the technique of metabolomics and then discusses how it and other omics techniques have been used to further our understanding of the basic biology of kidney cancer as well as to identify new therapeutic approaches.

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Metabolomics of oncogene-specific metabolic reprogramming during breast cancer.

Publications

Metabolomics of oncogene-specific metabolic reprogramming during breast cancer.

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