Glutamine Sensitivity Analysis Identifies the xCT Antiporter as a Common Triple-Negative Breast Tumor Therapeutic Target
Open accessAbstract
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.
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xc− may constitute a therapeutic target in triple-negative breast carcinoma.
“implying that xc− may constitute a therapeutic target in this setting [553, 554].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [553]
The pronounced addiction of triple-negative breast carcinoma to glutamine relates at least in part to its ability to drive cystine uptake via xc−.
“the pronounced addiction of triple-negative breast carcinoma to glutamine relates (at least in part) to its ability to drive cystine uptake via xc−, implying that xc− may constitute a therapeutic target in this setting [553, 554].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [553]
Glutamine starvation is associated with impaired uptake of cystine through xCT and decreased intracellular glutathione levels.
“Consistent with this observation, glutamine starvation has been associated with impaired uptake of cystine through xCT and decreased intracellular glutathione levels62.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [62]
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- Authors
- Timmerman, L. A., Holton, T., Yuneva, M., Louie, R. J., Padró, M., Daemen, A., Hu, M., Chan, D. A., Ethier, S. P., van ‘t Veer, L. J., Polyak, K., McCormick, F., & Gray, J. W.
- Affiliations
- University of California, San Francisco (US)
- San Francisco State University (US)
- Medical Research Council (GB)
- Novartis (China) (CN)
- Medical University of South Carolina (US)
- Oregon Health & Science University (US)
- Corresponding author
- Timmerman, Luika A.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 24
- Issue
- 4
- Pages
- 450-465
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3931310
- OpenAlex
- W2034530633
- Cited by
- 573
- References
- 61
- Citations by year
- 2026: 21 · 2025: 46 · 2024: 50 · 2023: 51 · 2022: 49 · 2021: 75 · 2020: 56 · 2019: 55 · 2018: 37 · 2017: 39 · 2016: 39 · 2015: 33 · 2014: 21
- FWCI
- 10.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- University of California, San Francisco
- National Cancer Institute (P50CA058207, U54CA112970)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Keywords
- triple-negative breast cancer, glutamine addiction, glutamine uptake, sulfasalazine, therapeutic target, breast cancer cell lines, cancer metabolism, drug development
- MeSH terms
- Animals, Female, Glutamine, Glutathione, Humans, Prognosis, Gene Expression Regulation, Neoplastic, Reactive Oxygen Species, Disease Progression, Gene Expression Profiling, Amino Acid Transport System y+, RNA, Small Interfering, Cell Line, Tumor, Mice, Triple Negative Breast Neoplasms
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