MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis
Atsushi Terunuma, … , Arun Sreekumar, Stefan Ambs
Atsushi Terunuma, … , Arun Sreekumar, Stefan Ambs
Published December 9, 2013
Citation Information: J Clin Invest. 2014;124(1):398-412. https://doi.org/10.1172/JCI71180.
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Research Article Oncology

MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis

Abstract

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.

Authors

Atsushi Terunuma, Nagireddy Putluri, Prachi Mishra, Ewy A. Mathé, Tiffany H. Dorsey, Ming Yi, Tiffany A. Wallace, Haleem J. Issaq, Ming Zhou, J. Keith Killian, Holly S. Stevenson, Edward D. Karoly, King Chan, Susmita Samanta, DaRue Prieto, Tiffany Y.T. Hsu, Sarah J. Kurley, Vasanta Putluri, Rajni Sonavane, Daniel C. Edelman, Jacob Wulff, Adrienne M. Starks, Yinmeng Yang, Rick A. Kittles, Harry G. Yfantis, Dong H. Lee, Olga B. Ioffe, Rachel Schiff, Robert M. Stephens, Paul S. Meltzer, Timothy D. Veenstra, Thomas F. Westbrook, Arun Sreekumar, Stefan Ambs

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Figure 4

Gene signatures for subgroup III and 2HG-high tumors are predictors of poor survival.

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Gene signatures for subgroup III and 2HG-high tumors are predictors of p...
(A) Association between the gene signature for subgroup III and breast cancer survival. Survival of patients with the gene expression signature of subgroup III (Subgroup III signature-high) was significantly decreased in 3 independent datasets (van de Vijver, ref. 2, n = 295; Kao, ref. 63, n = 327; Chin, Pawitan, Miller, and Desmedt, refs. 64–67, n = 710). To generate the subtype III gene expression signature, subtype III and subtype I breast tumors were compared to identify 159 and 296 genes that were consistently up- and downregulated, respectively, in subtype III tumors. (B) Association between the gene signature for 2HG-high tumors and breast cancer survival. Survival of patients with the gene expression signature of 2HG-high tumors (2HG signature-high) was significantly decreased in the 3 independent datasets shown in A. Breast tumors with high levels of 2HG (top 33%) and low levels of 2HG (lowest 33%) were compared to identify 50 and 127 genes that were consistently up- and downregulated, respectively, in 2HG-high tumors. Kaplan-Meier curves with Cox regression analysis results are shown.