The xCT Antiporter Is a Potential Therapeutic Target in TNBC

Enhanced reliance on glucose or glutamine is a common feature of many tumors, suggesting inhibition of key metabolic enzymes as a therapeutic strategy. However, nutrient utilization in tumors is heterogeneous, and a comprehensive analysis of responses to metabolic perturbations in breast cancer is lacking, prompting Timmerman and colleagues to determine the gene expression profiles and nutrient dependencies of a large panel of breast cancer cell lines compared with those of nontumorigenic human mammary epithelial cells. Although glucose consumption was highest in luminal tumors, and triple-negative breast cancers (TNBC) consumed higher amounts of glutamine, nutrient dependencies varied widely. Glutamine restriction reduced the expansion rate of the majority of breast cancer cells but induced S-phase stalling in a subset of TNBC cell lines, which did not expand or underwent apoptosis in response to glutamine deprivation. Expression of genes that regulate glutamine metabolism was not sufficient to identify this subset of TNBC cells, and supplementation with alternative carbon sources was unable to rescue these cells from glutamine restriction, indicating that these cells are glutamine auxotrophs that cannot synthesize the required amount of this nutrient. These auxotrophic cell lines were sensitive to therapeutic agents that blocked glutamine access or inhibited glutamine-utilizing enzymes. In addition, glutamine restriction decreased cystine/glutamate exchange via solute carrier family 7 (anionic amino acid transporter light chain, xc- system), member 11 (SLC7A11, also known as xCT), which is required for synthesis of the antioxidant glutathione and was upregulated in TNBC cells. Depletion or pharmacologic inhibition of xCT reduced glutathione levels, increased intracellular reactive oxygen species, diminished the growth of auxotrophic TNBC xenografts, and enhanced the sensitivity of TNBC cells to carboplatin. These findings provide insight into the metabolic activities of breast cancer cells and identify xCT as a potential therapeutic target in TNBC.

Timmerman LA, Holton T, Yuneva M, Louie RJ, Padró M, Daemen A, et al. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell 2013 Oct 3 [Epub ahead of print].

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