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.
View: Text | PDF
Research Article Oncology Article has an altmetric score of 41

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

×

Figure 7

Association of tumor glutamine levels with breast cancer survival.

Options: View larger image (or click on image) Download as PowerPoint
Association of tumor glutamine levels with breast cancer survival. (A) P...
(A) Patients with low tumor glutamine levels (Gln-low) exhibited poor outcome in the discovery and validation sets (both with stratification at lowest 25% vs. highest 75%). (B) Survival of patients with the gene expression signature of glutamine-low tumors (Gln-low signature-high) was significantly decreased compared with patients that did not have this tumor signature in 3 publicly available datasets (van de Vijver, ref. 2; Kao, ref. 63; Chin, Pawitan, Miller, and Desmedt, refs. 64–67). Breast tumors with low and high glutamine levels were compared (lowest vs. highest quartile) to identify 8 and 25 genes that were consistently up- and downregulated, respectively, in glutamine-low tumors. This 33-gene expression signature for glutamine-low tumors was then applied. Kaplan-Meier curves with Cox regression results are shown.