Glutamine addiction promotes glucose oxidation in triple-negative breast cancer

Abstract

Glutamine is a conditionally essential nutrient for many cancer cells, but it remains unclear how consuming glutamine in excess of growth requirements confers greater fitness to glutamine-addicted cancers. By contrasting two breast cancer subtypes with distinct glutamine dependencies, we show that glutamine-indispensable triple-negative breast cancer (TNBC) cells rely on a non-canonical glutamine-to-glutamate overflow, with glutamine carbon routed once through the TCA cycle. Importantly, this single-pass glutaminolysis increases TCA cycle fluxes and replenishes TCA cycle intermediates in TNBC cells, a process that achieves net oxidation of glucose but not glutamine. The coupling of glucose and glutamine catabolism appears hard-wired via a distinct TNBC gene expression profile biased to strip and then sequester glutamine nitrogen, but hampers the ability of TNBC cells to oxidise glucose when glutamine is limiting. Our results provide a new understanding of how metabolically rigid TNBC cells are sensitive to glutamine deprivation and a way to select vulnerable TNBC subtypes that may be responsive to metabolic-targeted therapies.

Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer

“…TYMS expression was elevated in breast cancer compared with normal tissues, and was greater in TNBC than non-TNBC, and higher TYMS was associated with poor prognosis [ 112 ]. Consistent with this, purine/pyrimidine metabolism enzyme gene sets are elevated in TNBC [ 89 ]. Dihydrofolate reductase (DHFR), another enzyme in folate metabolism, is essential to purine synthesis and contribute to mitochondrial thymidylate biosynthesis.…”

“…Glutamine metabolism is promoted by PGC1α in HER2+ breast cancer [ 83 ]. TNBC are known to be “glutamine-addicted”, with higher expression of key enzymes mediators of glutamine metabolism, including GLS, amino acid transporter-2 (ASCT2) [ 84 , 85 , 86 , 87 , 88 , 89 ]. Glutamate is enriched in breast cancer tissue [ 90 ].…”

Screening and diagnosis of triple negative breast cancer based on rapid metabolic fingerprinting by conductive polymer spray ionization mass spectrometry and machine learning

“…Among these metabolites, glutamine has been extensively reported as a conditionally essential nutrient for many cancer cells, which is termed as “glutamine addiction.” Glutamine has been reported to serves as a supplement for energy fueling in TNBC by incorporating into the Krebs cycle through glutaminolysis into glutamate and thereafter deamination into 2-ketoglutarate ( Quek, L.E., et al, 2022 ). There were higher levels of arginine ( m/z 175.1190, [M + H] + ) and lysine ( m/z 147.1128, [M + H] + ) in TNBCs.…”

A Tale of Three Proteomes: Visualizing Protein and Transcript Abundance Relationships in the Breast Cancer Proteome Portal

“…The power of applying the Breast Cancer Proteome Portal visualization tools is illustrated by unearthing evidence for unexplored regulatory mechanisms of both one-carbon and glutamine metabolism. Both are of importance because, while their relevance is established, their modes of action in driving breast tumorigenesis are incompletely understood. , Furthermore, observed tight correlations across tumors of known subunits of protein complexes lend confidence that correlation is an indicator of cofunction. Thus, informatic analyses of protein expression data can guide the design and target selection of resource-intensive studies focused on therapy development and improvement.…”