MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis
Open accessAbstract
Metabolic profiling of cancer cells has recently been established as a promising tool for the development of therapies and identification of cancer biomarkers. Here we characterized the metabolomic profile of human breast tumors and uncovered intrinsic metabolite signatures in these tumors using an untargeted discovery approach and validation of key metabolites. The oncometabolite 2-hydroxyglutarate (2HG) accumulated at high levels in a subset of tumors and human breast cancer cell lines. We discovered an association between increased 2HG levels and MYC pathway activation in breast cancer, and further corroborated this relationship using MYC overexpression and knockdown in human mammary epithelial and breast cancer cells. Further analyses revealed globally increased DNA methylation in 2HG-high tumors and identified a tumor subtype with high tissue 2HG and a distinct DNA methylation pattern that was associated with poor prognosis and occurred with higher frequency in African-American patients. Tumors of this subtype had a stem cell-like transcriptional signature and tended to overexpress glutaminase, suggestive of a functional relationship between glutamine and 2HG metabolism in breast cancer. Accordingly, 13C-labeled glutamine was incorporated into 2HG in cells with aberrant 2HG accumulation, whereas pharmacologic and siRNA-mediated glutaminase inhibition reduced 2HG levels. Our findings implicate 2HG as a candidate breast cancer oncometabolite associated with MYC activation and poor prognosis.
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The reviewed studies suggest involvement of Myc in the production of 2-HG.
“The above studies suggest the involvement of Myc in the production of 2-HG.”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [174]
Elevated 2-HG levels have been detected in triple-negative breast cancer.
“For instance, elevated 2-HG levels have been detected in triple-negative breast cancer (Terunuma et al., 2014).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Terunuma et al., 2014
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- The Pawitan, Miller, Desmedt, and Chin datasets (64-67) were combined into a single matrix. See Supple- mental Methods for details. Study approval. The collection of biospecimens and the clinical and pathological information was approved by the University of Maryland Institutional Review Board for the participating institutions (UMD pro- tocol no. 0298229). IRB approval of this protocol was then obtained at all institutions (Veterans Affairs Medical Center, Union Memorial Hospital, Mercy Medical Center, and Sinai Hospital, Baltimore, Maryland, USA). The research was also reviewed and approved by the NIH Office of Human Sub- jects Research Protections (OHSRP no. 2248). All patients signed a consent form and completed an interviewer-administered questionnaire.
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- Authors
- Terunuma, A., Putluri, N., Mishra, P., Mathé, E. A., Dorsey, T. H., Yi, M., Wallace, T. A., Issaq, H. J., Zhou, M., Killian, J. K., Stevenson, H. S., Karoly, E. D., Chan, K., Samanta, S., Prieto, D., Hsu, T. Y. T., Kurley, S. J., Putluri, V., Sonavane, R., Edelman, D. C., Wulff, J., Starks, A. M., Yang, Y., Kittles, R. A., Yfantis, H. G., Lee, D. H., Ioffe, O. B., Schiff, R., Stephens, R. M., Meltzer, P. S., Veenstra, T. D., Westbrook, T. F., Sreekumar, A., & Ambs, S.
- Affiliations
- National Institutes of Health (US)
- Alkek Center for Molecular Discovery (US)
- Baylor College of Medicine (US)
- Frederick National Laboratory for Cancer Research (US)
- Metabolon (United States) (US)
- University of Illinois Chicago (US)
- Baltimore VA Medical Center (US)
- University of Maryland, Baltimore (US)
- ORCID
- Putluri, Nagireddy
- Mathé, Ewy A.
- Dorsey, Tiffany H.
- Yi, Ming
- Wallace, Tiffany A.
- Zhou, Ming
- Stevenson, Holly S.
- Karoly, Edward D.
- Samanta, Susmita
- Hsu, Tiffany Y.T.
- Kurley, Sarah J.
- Putluri, Vasanta
- Edelman, Daniel C.
- Wulff, Jacob
- Starks, Adrienne M.
- Yang, Yinmeng
- Kittles, Rick A.
- Lee, Dong H.
- Ioffe, Olga B.
- Schiff, Rachel
- Meltzer, Paul S.
- Veenstra, Timothy D.
- Westbrook, Thomas F.
- Sreekumar, Arun
- Ambs, Stefan
- Venue
- Journal of Clinical Investigation
- Published
- 2013-12-09
- Volume
- 124
- Issue
- 1
- Pages
- 398-412
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3871244
- OpenAlex
- W2044055595
- Cited by
- 428
- References
- 75
- Citations by year
- 2026: 13 · 2025: 25 · 2024: 25 · 2023: 44 · 2022: 24 · 2021: 50 · 2020: 34 · 2019: 43 · 2018: 49 · 2017: 29 · 2016: 36 · 2015: 38 · 2014: 18
- FWCI
- 10.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA 58183, F30CA180447, R01CA133458, SPORE CA58183, U01CA167234, P50CA058183)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- 2-hydroxyglutarate, c-Myc, breast cancer, oncometabolites, DNA methylation, prognostic factors, glutaminase, glutamine metabolism, cancer stemness, African American patients, tumor subtypes, cancer metabolism
- MeSH terms
- Alcohol Oxidoreductases, Breast Neoplasms, Female, Glutamine, Glutarates, Humans, Isocitrate Dehydrogenase, Mitochondria, Prognosis, Receptors, Estrogen, Gene Expression Regulation, Neoplastic, Survival Analysis, Proto-Oncogene Proteins c-myc, Apoptosis, DNA Methylation, Mitochondrial Proteins, RNA, Small Interfering, Metabolome, Gene Knockdown Techniques, Transcriptome, Wnt Signaling Pathway, MCF-7 Cells
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