title: Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells.
abstract: Triple negative breast cancers (TNBCs) are defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 expression, and are treated with cytotoxic chemotherapy such as paclitaxel or gemcitabine, with a durable response rate of less than 20%. TNBCs are enriched for the basal subtype gene expression profile and the presence of breast cancer stem cells, which are endowed with self-renewing and tumor-initiating properties and resistance to chemotherapy. Hypoxia-inducible factors (HIFs) and their target gene products are highly active in TNBCs. Here, we demonstrate that HIF expression and transcriptional activity are induced by treatment of MDA-MB-231, SUM-149, and SUM-159, which are human TNBC cell lines, as well as MCF-7, which is an ER(+)/PR(+) breast cancer line, with paclitaxel or gemcitabine. Chemotherapy-induced HIF activity enriched the breast cancer stem cell population through interleukin-6 and interleukin-8 signaling and increased expression of multidrug resistance 1. Coadministration of HIF inhibitors overcame the resistance of breast cancer stem cells to paclitaxel or gemcitabine, both in vitro and in vivo, leading to tumor eradication. Increased expression of HIF-1α or HIF target genes in breast cancer biopsies was associated with decreased overall survival, particularly in patients with basal subtype tumors and those treated with chemotherapy alone. Based on these results, clinical trials are warranted to test whether treatment of patients with TNBC with a combination of cytotoxic chemotherapy and HIF inhibitors will improve patient survival.
authors.affiliation: Vascular Program, Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and.
authors.forename: Debangshu
authors.initials: D
authors.lastname: Samanta
authors.affiliation: Vascular Program, Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and.
authors.forename: Daniele M
authors.initials: DM
authors.lastname: Gilkes
authors.affiliation: Vascular Program, Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Chaturvedi
authors.affiliation: Vascular Program, Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Lisha
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Vascular Program, Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and gsemenza@jhmi.edu.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000704:Analysis of Variance; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D015151:Immunoblotting; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008156:Luciferases; D008853:Microscopy; D017239:Paclitaxel / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D017931:DNA Primers; D051793:Hypoxia-Inducible Factor 1; D015850:Interleukin-6; D016209:Interleukin-8; D003841:Deoxycytidine; D008156:Luciferases; D017239:Paclitaxel; D000093542:Gemcitabine
keywords: digoxin; mammary fat pad implantation; tumor relapse