title: A function-blocking CD47 antibody suppresses stem cell and EGF signaling in triple-negative breast cancer.
abstract: CD47 is a signaling receptor for thrombospondin-1 and the counter-receptor for signal-regulatory protein-α (SIRPα). By inducing inhibitory SIRPα signaling, elevated CD47 expression by some cancers prevents macrophage phagocytosis. The anti-human CD47 antibody B6H12 inhibits tumor growth in several xenograft models, presumably by preventing SIRPα engagement. However, CD47 signaling in nontransformed and some malignant cells regulates self-renewal, suggesting that CD47 antibodies may therapeutically target cancer stem cells (CSCs). Treatment of MDA-MB-231 breast CSCs with B6H12 decreased proliferation and asymmetric cell division. Similar effects were observed in T47D CSCs but not in MCF7 breast carcinoma or MCF10A breast epithelial cells. Gene expression analysis in breast CSCs treated with B6H12 showed decreased expression of epidermal growth factor receptor (EGFR) and the stem cell transcription factor KLF4. EGFR and KLF4 mRNAs are known targets of microRNA-7, and B6H12 treatment correspondingly enhanced microRNA-7 expression in breast CSCs. B6H12 treatment also acutely inhibited EGF-induced EGFR tyrosine phosphorylation. Expression of B6H12-responsive genes correlated with CD47 mRNA expression in human breast cancers, suggesting that the CD47 signaling pathways identified in breast CSCs are functional in vivo. These data reveal a novel SIRPα-independent mechanism by which therapeutic CD47 antibodies could control tumor growth by autonomously forcing differentiation of CSC.
authors: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Sukhbir
authors: S
authors: Kaur
authors: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Abdel G
authors: AG
authors: Elkahloun
authors: Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: Satya P
authors: SP
authors: Singh
authors: Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Qing-Rong
authors: QR
authors: Chen
authors: Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Daoud M
authors: DM
authors: Meerzaman
authors: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Timothy
authors: T
authors: Song
authors: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Nidhi
authors: N
authors: Manu
authors: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Weiwei
authors: W
authors: Wu
authors: Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Poonam
authors: P
authors: Mannan
authors: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Susan H
authors: SH
authors: Garfield
authors: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: David D
authors: DD
authors: Roberts
mesh_terms: D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D051928:CD47 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D000090062:Kruppel-Like Factor 4; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics; D018613:Microscopy, Confocal; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D019138:Antibodies, Blocking; D000943:Antigens, Differentiation; D051928:CD47 Antigen; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000090062:Kruppel-Like Factor 4; D035683:MicroRNAs; D011971:Receptors, Immunologic; D019700:Thrombospondin 1; C497894:CD47 protein, human; C000715467:KLF4 protein, human; C549242:MIRN7-1 microRNA, human; C501920:SIRPA protein, human; C000611726:thrombospondin-1, human
keywords: CD47; cancer stem cells; epidermal growth factor receptor; therapeutic antibodies; triple-negative breast cancer