Glutamine Sensitivity Analysis Identifies the xCT Antiporter as a Common Triple-Negative Breast Tumor Therapeutic Target

A handful of tumor-derived cell lines form the mainstay of cancer therapeutic development, yielding drugs with an impact typically measured as months to disease progression. To develop more effective breast cancer therapeutics and more readily understand their clinical impact, we constructed a funct...

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Published inCancer cell Vol. 24; no. 4; pp. 450 - 465
Main Authors Timmerman, Luika A., Holton, Thomas, Yuneva, Mariia, Louie, Raymond J., Padró, Mercè, Daemen, Anneleen, Hu, Min, Chan, Denise A., Ethier, Stephen P., van ‘t Veer, Laura J., Polyak, Kornelia, McCormick, Frank, Gray, Joe W.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 14.10.2013
Subjects
Amino Acid Transport System y+ - metabolism
Animals
Cell Line, Tumor
Disease Progression
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Glutamine - metabolism
Glutamine - pharmacology
Glutathione - metabolism
Humans
Mice
Prognosis
Reactive Oxygen Species
RNA, Small Interfering - metabolism
Triple Negative Breast Neoplasms - metabolism
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Summary:A handful of tumor-derived cell lines form the mainstay of cancer therapeutic development, yielding drugs with an impact typically measured as months to disease progression. To develop more effective breast cancer therapeutics and more readily understand their clinical impact, we constructed a functional metabolic portrait of 46 independently derived breast cell lines. Our analysis of glutamine uptake and dependence identified a subset of triple-negative samples that are glutamine auxotrophs. Ambient glutamine indirectly supports environmental cystine acquisition via the xCT antiporter, which is expressed on one-third of triple-negative tumors in vivo. xCT inhibition with the clinically approved anti-inflammatory sulfasalazine decreases tumor growth, revealing a therapeutic target in breast tumors of poorest prognosis and a lead compound for rapid, effective drug development. •Most breast tumors survive glutamine restriction, limiting its therapeutic use•A subset of triple-negative breast tumors are true glutamine auxotrophs•Conventional biomarkers of glutamine reliance do not identify true auxotrophs•Triple-negative tumors require cystine import via the xCT transporter
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These authors contributed equally to this work
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2013.08.020