title: 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
authors: A
authors: Terunuma
authors: Nagireddy
authors: N
authors: Putluri
authors: Prachi
authors: P
authors: Mishra
authors: Ewy A
authors: EA
authors: Mathé
authors: Tiffany H
authors: TH
authors: Dorsey
authors: Ming
authors: M
authors: Yi
authors: Tiffany A
authors: TA
authors: Wallace
authors: Haleem J
authors: HJ
authors: Issaq
authors: Ming
authors: M
authors: Zhou
authors: J Keith
authors: JK
authors: Killian
authors: Holly S
authors: HS
authors: Stevenson
authors: Edward D
authors: ED
authors: Karoly
authors: King
authors: K
authors: Chan
authors: Susmita
authors: S
authors: Samanta
authors: DaRue
authors: D
authors: Prieto
authors: Tiffany Y T
authors: TY
authors: Hsu
authors: Sarah J
authors: SJ
authors: Kurley
authors: Vasanta
authors: V
authors: Putluri
authors: Rajni
authors: R
authors: Sonavane
authors: Daniel C
authors: DC
authors: Edelman
authors: Jacob
authors: J
authors: Wulff
authors: Adrienne M
authors: AM
authors: Starks
authors: Yinmeng
authors: Y
authors: Yang
authors: Rick A
authors: RA
authors: Kittles
authors: Harry G
authors: HG
authors: Yfantis
authors: Dong H
authors: DH
authors: Lee
authors: Olga B
authors: OB
authors: Ioffe
authors: Rachel
authors: R
authors: Schiff
authors: Robert M
authors: RM
authors: Stephens
authors: Paul S
authors: PS
authors: Meltzer
authors: Timothy D
authors: TD
authors: Veenstra
authors: Thomas F
authors: TF
authors: Westbrook
authors: Arun
authors: A
authors: Sreekumar
authors: Stefan
authors: S
authors: Ambs
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005973:Glutamine / Q000378:metabolism; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D055442:Metabolome; D008928:Mitochondria / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism; D016019:Survival Analysis; D059467:Transcriptome; D060449:Wnt Signaling Pathway
chemical_list: D005977:Glutarates; C489427:MYC protein, human; D024101:Mitochondrial Proteins; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D005973:Glutamine; C019417:alpha-hydroxyglutarate; D000429:Alcohol Oxidoreductases; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C072878:hydroxyacid-oxoacid transhydrogenase