Chemotherapy triggers HIF-1–dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype

Significance We demonstrate that glutathione biosynthesis is controlled by hypoxia-inducible factor 1 and is critical for chemotherapy-induced enrichment of breast cancer stem cells, making it an attractive therapeutic target in triple-negative breast cancer, which is the only subset of breast cancers for which there is no available targeted therapy. We also delineate a molecular mechanism in which glutathione functions as a signaling molecule to activate the breast cancer stem cell phenotype, establishing cross-talk between cancer metabolism and signal transduction. We also demonstrate that mitogen-activated protein kinase kinase (MEK)-ERK inhibitors and copper chelators have the countertherapeutic effect of inducing breast cancer stem cell enrichment.