Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia
Open accessAbstract
Although significant variations in the metabolic profiles exist among different cells, little is understood in terms of genetic regulations of such cell type-specific metabolic phenotypes and nutrient requirements. While many cancer cells depend on exogenous glutamine for survival to justify the therapeutic targeting of glutamine metabolism, the mechanisms of glutamine dependence and likely response and resistance of such glutamine-targeting strategies among cancers are largely unknown. In this study, we have found a systematic variation in the glutamine dependence among breast tumor subtypes associated with mammary differentiation: basal- but not luminal-type breast cells are more glutamine-dependent and may be susceptible to glutamine-targeting therapeutics. Glutamine independence of luminal-type cells is associated mechanistically with lineage-specific expression of glutamine synthetase (GS). Luminal cells can also rescue basal cells in co-culture without glutamine, indicating a potential for glutamine symbiosis within breast ducts. The luminal-specific expression of GS is directly induced by GATA3 and represses glutaminase expression. Such distinct glutamine dependency and metabolic symbiosis is coupled with the acquisition of the GS and glutamine independence during the mammary differentiation program. Understanding the genetic circuitry governing distinct metabolic patterns is relevant to many symbiotic relationships among different cells and organisms. In addition, the ability of GS to predict patterns of glutamine metabolism and dependency among tumors is also crucial in the rational design and application of glutamine and other metabolic pathway targeted therapies.
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Most basal breast cancer cells require glutamine supplementation in media, whereas luminal breast cancers are less glutamine dependent.
“most basal breast cancer cells require glutamine supplementation in the media, whereas luminal breast cancers are less glutamine dependent [76].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [76]
Some cell types, such as embryonic stem cells and luminal breast cancer cells, can proliferate without glutamine in culture medium, indicating de novo glutamine production in some contexts.
“Interestingly, some cell types, such as embryonic stem cells and luminal breast cancer cells, are capable of proliferating in the absence of glutamine in the culture medium, indicating that in some cellular contexts, glutamine can be produced de novo (Carey et al., 2015; Kung et al., 2011).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Kung et al., 2011
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BackgroundMetabolic reprogramming in triple-negative breast cancer
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Van Nguyen, T., Lee, J. E., Sweredoski, M. J., Yang, S.-J., Jeon, S.-J., Harrison, J. S., Yim, J.-H., Lee, S. G., Handa, H., Kuhlman, B., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.02.032 · Cited by 177 · see citing works
“linked to human diseases, including congenital glutamine deficiency, Alzheimer’s disease, and cancers (Bott et al., 2015; Christa et al., 1994; Gunnersen and Haley, 1992; Haberle et al., 2005; Kung et al., 2011; Tardito et al., 2015).”
The role of ASCT2 in cancer: A review
Liu, Y., Zhao, T., Li, Z., Wang, L., Yuan, S., & Sun, L. (2018) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2018.07.007 · Cited by 162 · see citing works
HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells
Lee, S.-H., Golinska, M., & Griffiths, J. R. (2021) · Cells · doi:10.3390/cells10092371 · Cited by 169 · see citing works
Alternative fuels for cancer cells
Keenan, M. M., & Chi, J.-T. (2015) · The Cancer Journal · doi:10.1097/ppo.0000000000000104 · Cited by 131 · see citing works
Self-citationp97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates
Nguyen, T. V., Li, J., Lu, C.-C. (., Mamrosh, J. L., Lu, G., Cathers, B. E., & Deshaies, R. J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1700949114 · Cited by 85 · see citing works
Glutamine as an Essential Amino Acid for KRas-Driven Cancer Cells
Bernfeld, E., & Foster, D. A. (2019) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2019.03.003 · Cited by 85 · see citing works
Lucantoni, F., Dussmann, H., & Prehn, J. H. M. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00113 · Cited by 47 · see citing works
“Indeed, both TNBC and HER2+ subtypes possess increased glutamine consumption and glutaminolysis levels (Kung et al., 2011; Kim et al., 2013; Lampa et al., 2017).”
Background
- Authors
- Kung, H.-N., Marks, J. R., & Chi, J.-T.
- Affiliations
- National Taiwan University (TW)
- Duke Medical Center (US)
- Corresponding author
- Chi, Jen-Tsan
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-08-11
- Volume
- 7
- Issue
- 8
- Pages
- e1002229
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3154963
- OpenAlex
- W2056648518
- Cited by
- 277
- References
- 66
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 14 · 2023: 21 · 2022: 20 · 2021: 34 · 2020: 21 · 2019: 27 · 2018: 16 · 2017: 19 · 2016: 26 · 2015: 19 · 2014: 19 · 2013: 16 · 2012: 9
- FWCI
- 4.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA125618, U01CA084955, UO1CA084955)
- 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 › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- glutamine synthetase, glutamine addiction, breast epithelium, mammary gland differentiation, basal-like breast cancer, luminal breast cancer, GATA3, glutaminase, metabolic symbiosis, cell type-specific metabolism, tumor subtypes
- MeSH terms
- Breast, Breast Neoplasms, Cell Differentiation, Cell Survival, Culture Media, Epithelium, Female, Glutaminase, Glutamine, Glutamate-Ammonia Ligase, Humans, Nutritional Physiological Phenomena, Phenotype, Promoter Regions, Genetic, Gene Expression, Gene Expression Regulation, Neoplastic, Coculture Techniques, Cell Lineage, Gene Expression Profiling, Cell Line, Tumor, Cell Proliferation, GATA3 Transcription Factor, Molecular Targeted Therapy
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