Fig. 7.

Pluripotency factor expression and the BCSC phenotype are induced through HIF-1–dependent glutathione synthesis in response to chemotherapy. Chemotherapy treatment induces HIF-1–dependent SLC7A11 and GCLM transcriptional activation, leading to increased glutathione synthesis. Glutathione chelates copper, which is a required cofactor for MEK1, leading to inactivation of MEK1-ERK signaling, FoxO3 dephosphorylation, and nuclear translocation, leading to transcriptional activation of NANOG, which encodes a pluripotency factor that specifies the BCSC phenotype.