title: Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype.
abstract: Triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancer but is responsible for a disproportionate share of morbidity and mortality because of its aggressive characteristics and lack of targeted therapies. Chemotherapy induces enrichment of breast cancer stem cells (BCSCs), which are responsible for tumor recurrence and metastasis. Here, we demonstrate that chemotherapy induces the expression of the cystine transporter xCT and the regulatory subunit of glutamate-cysteine ligase (GCLM) in a hypoxia-inducible factor (HIF)-1-dependent manner, leading to increased intracellular glutathione levels, which inhibit mitogen-activated protein kinase kinase (MEK) activity through copper chelation. Loss of MEK-ERK signaling causes FoxO3 nuclear translocation and transcriptional activation of the gene encoding the pluripotency factor Nanog, which is required for enrichment of BCSCs. Inhibition of xCT, GCLM, FoxO3, or Nanog blocks chemotherapy-induced enrichment of BCSCs and impairs tumor initiation. These results suggest that, in combination with chemotherapy, targeting BCSCs by inhibiting HIF-1-regulated glutathione synthesis may improve outcome in TNBC.
authors.affiliation: Johns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Haiquan
authors.initials: H
authors.lastname: Lu
authors.affiliation: Johns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Debangshu
authors.initials: D
authors.lastname: Samanta
authors.affiliation: Johns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Lisha
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Johns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Huimin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Johns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Hongxia
authors.initials: H
authors.lastname: Hu
authors.affiliation: Johns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Ivan
authors.initials: I
authors.lastname: Chen
authors.affiliation: Johns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: John W
authors.initials: JW
authors.lastname: Bullen
authors.affiliation: Johns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 gsemenza@jhmi.edu.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry; D003300:Copper / Q000737:chemistry*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology*; D009841:Oligonucleotides / Q000235:genetics; D017239:Paclitaxel / Q000737:chemistry; D010641:Phenotype; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009841:Oligonucleotides; D012333:RNA, Messenger; D003300:Copper; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D005978:Glutathione; D017239:Paclitaxel
keywords: chemotherapy resistance; hypoxia-inducible factor; paclitaxel; pluripotency factors; tumor-initiating cells