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. Different types of cells have distinct ways of utilizing nutrients and generating energy, thus resulting in distinct nutrient needs. Such cell type–specific metabolic differences are associated with many biological processes and force the symbiosis between different cells and organisms. For example, glutamine symbiosis is a well-recognized phenomenon due to different glutamine synthesis ability. In human cancers, glutamine is also recognized as an important and essential nutrient, termed glutamine addiction. But very little is known about how glutamine addiction varies among different tumors of diverse cellular origins, which hinders personalized therapeutic strategies. Here, we found that basal-type breast cancer cells were sensitive to glutamine deprivation while luminal-type breast cancer cells were not. Luminal cell–specific glutamine independence results from expression of glutamine synthetase conferring the ability to synthesize glutamine. Glutamine synthetase also represses glutaminase and contributes to the maintenance of the polarized expression of glutamine synthetase and glutaminase among breast cancer cells. Collectively, these data illustrate cross-talk between mammary differentiation programs and unique nutrient requirements, which may offer novel therapeutics for basal-type breast cancers.