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 2

Aberrant accumulation of 2HG in breast cancer and its relationship with genome-wide DNA methylation in breast tumors.

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Aberrant accumulation of 2HG in breast cancer and its relationship with ...
(A) Relative abundance of 2HG in breast tumors and adjacent noncancerous tissue for all paired samples (n = 65, 33 ER-positive and 32 ER-negative) for the discovery set. (B) 2HG quantitation for ER-negative tumor (n = 60) and adjacent noncancerous tissue (n = 29) in the validation set. P value was determined by paired t test (n = 29). Relative abundance of 2HG in 3 benign and 14 cancerous human breast cell lines is also shown. (C) Normalized genome-wide DNA methylation scores were calculated for breast tumors in the discovery set using Human Methylation 450 BeadChips data. 2HG-high tumors (median and above) had a significantly higher DNA methylation score than 2HG-low tumors (below median), as determined by Welch t test.