title: HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells.
abstract: Increased expression of CD47 has been reported to enable cancer cells to evade phagocytosis by macrophages and to promote the cancer stem cell phenotype, but the molecular mechanisms regulating CD47 expression have not been determined. Here we report that hypoxia-inducible factor 1 (HIF-1) directly activates transcription of the CD47 gene in hypoxic breast cancer cells. Knockdown of HIF activity or CD47 expression increased the phagocytosis of breast cancer cells by bone marrow-derived macrophages. CD47 expression was increased in mammosphere cultures, which are enriched for cancer stem cells, and CD47 deficiency led to cancer stem cell depletion. Analysis of datasets derived from thousands of patients with breast cancer revealed that CD47 expression was correlated with HIF target gene expression and with patient mortality. Thus, CD47 expression contributes to the lethal breast cancer phenotype that is mediated by HIF-1.
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; 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: Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; 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: Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; 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: Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; 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: Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Chuanzhao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; 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: Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Daniele M
authors.initials: DM
authors.lastname: Gilkes
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China;
authors.forename: Jianjun
authors.initials: J
authors.lastname: He
authors.affiliation: Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of 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: D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000378:metabolism*; D051928:CD47 Antigen / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism* / Q000494:pharmacology; D015151:Immunoblotting; D008156:Luciferases; D014411:Neoplastic Stem Cells / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D019139:Tumor Escape / Q000502:physiology*
chemical_list: D051928:CD47 Antigen; C497894:CD47 protein, human; D017931:DNA Primers; D051793:Hypoxia-Inducible Factor 1; D034741:RNA, Small Interfering; D008156:Luciferases
keywords: antitumor immunity; immune evasion; tumor microenvironment; tumor-initiating cells; “don’t eat me” signal