title: A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer.
abstract: CD47 is a cell surface molecule that inhibits phagocytosis of cells that express it by binding to its receptor, SIRPα, on macrophages and other immune cells. CD47 is expressed at different levels by neoplastic and normal cells. Here, to reveal mechanisms by which different neoplastic cells generate this dominant 'don't eat me' signal, we analyse the CD47 regulatory genomic landscape. We identify two distinct super-enhancers (SEs) associated with CD47 in certain cancer cell types. We show that a set of active constituent enhancers, located within the two CD47 SEs, regulate CD47 expression in different cancer cell types and that disruption of CD47 SEs reduces CD47 gene expression. Finally we report that the TNF-NFKB1 signalling pathway directly regulates CD47 by interacting with a constituent enhancer located within a CD47-associated SE specific to breast cancer. These results suggest that cancers can evolve SE to drive CD47 overexpression to escape immune surveillance.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Paola A
authors.initials: PA
authors.lastname: Betancur
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Abraham
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Ying Y
authors.initials: YY
authors.lastname: Yiu
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Willingham
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Farnaz
authors.initials: F
authors.lastname: Khameneh
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Zarnegar
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Angera H
authors.initials: AH
authors.lastname: Kuo
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: McKenna
authors.affiliation: Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kojima
authors.affiliation: Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Leeper
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Po
authors.initials: P
authors.lastname: Ho
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Phung
authors.initials: P
authors.lastname: Gip
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Tomek
authors.initials: T
authors.lastname: Swigut
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115 USA.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Sherwood
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Clarke
authors.affiliation: Department of Medical Oncology &Therapeutics Research, City of Hope National Medical Center, Duarte, California 91010, USA.
authors.forename: George
authors.initials: G
authors.lastname: Somlo
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Richard A
authors.identifier: 0000-0001-8855-8647
authors.initials: RA
authors.lastname: Young
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D051928:CD47 Antigen / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D004742:Enhancer Elements, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D010587:Phagocytosis; D011485:Protein Binding; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051928:CD47 Antigen; C497894:CD47 protein, human; D018836:Inflammation Mediators; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D014409:Tumor Necrosis Factor-alpha