title: Slug/β-catenin-dependent proinflammatory phenotype in hypoxic breast cancer stem cells.
abstract: Cancer stem cell survival relies on the activation of inflammatory pathways, which is speculatively triggered by cell autonomous mechanisms or by microenvironmental stimuli. Here, we observed that hypoxic bone marrow stroma-derived transforming growth factor-β 1 promotes the growth of human breast cancer stem cells as mammospheres. The ensuing Slug-dependent serine 139 phosphorylation of the DNA damage sensor H2AX in breast cancer stem cells induces tumor necrosis factor-α and IL-8 mRNAs, whose stability is enhanced by cytoplasmic β-catenin. β-Catenin also up-regulates and binds miR-221, reducing the stability of the miR-221 targets Rad51 and ERα mRNAs. Our data show that the Slug/β-catenin-dependent activation of DNA damage signaling triggered by the hypoxic microenvironment sustains the proinflammatory phenotype of breast cancer stem cells.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy; Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, Bologna, Italy. Electronic address: gianluca.storci@unibo.it.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Storci
authors.affiliation: Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Bertoni
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy; Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: De Carolis
authors.affiliation: Department of Biological, Geological and Environmental Sciences, Functional Genomics Center, University of Verona, Verona, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Papi
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Nati
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceccarelli
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pirazzini
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Garagnani
authors.affiliation: Department of Biotechnologies, Functional Genomics Center, University of Verona, Verona, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ferrarini
authors.affiliation: Department of Biotechnologies, Functional Genomics Center, University of Verona, Verona, Italy.
authors.forename: Genny
authors.initials: G
authors.lastname: Buson
authors.affiliation: Department of Biotechnologies, Functional Genomics Center, University of Verona, Verona, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Delledonne
authors.affiliation: Pathology Unit, Addarii Institute of Oncology, St. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Fiorentino
authors.affiliation: Pathology Unit, Addarii Institute of Oncology, St. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Capizzi
authors.affiliation: Pathology Unit, Addarii Institute of Oncology, St. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gruppioni
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Taffurelli
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Santini
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Franceschi
authors.affiliation: Institute of Haematology "L & A Seragnoli", St. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bandini
authors.affiliation: Institute of Haematology "L & A Seragnoli", St. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bonifazi
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy; Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, Bologna, Italy. Electronic address: massimiliano.bonafe@unibo.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonafé
mesh_terms: D019898:Autocrine Communication / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D061986:MCF-7 Cells; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000071250:Snail Family Transcription Factors; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D016207:Cytokines; C468783:H2AX protein, human; D006657:Histones; D012333:RNA, Messenger; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D012694:Serine; D051135:Rad51 Recombinase