title: Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia.
abstract: 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.
authors.affiliation: Duke Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Hsiu-Ni
authors.initials: HN
authors.lastname: Kung
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Marks
authors.forename: Jen-Tsan
authors.initials: JT
authors.lastname: Chi
mesh_terms: D001940:Breast / Q000201:enzymology* / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation; D002470:Cell Survival; D018920:Coculture Techniques; D003470:Culture Media; D004848:Epithelium / Q000201:enzymology*; D005260:Female; D050990:GATA3 Transcription Factor / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005974:Glutamate-Ammonia Ligase / Q000235:genetics* / Q000378:metabolism; D005972:Glutaminase / Q000235:genetics* / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D058990:Molecular Targeted Therapy; D009747:Nutritional Physiological Phenomena; D010641:Phenotype; D011401:Promoter Regions, Genetic
chemical_list: D003470:Culture Media; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D005973:Glutamine; D005972:Glutaminase; D005974:Glutamate-Ammonia Ligase