title: Intracellular STING inactivation sensitizes breast cancer cells to genotoxic agents.
abstract: Activation of the IFN/STAT1 pathway is closely associated with drug response and recurrence of breast cancer treated by chemotherapy. The aim of the current study was to elucidate the molecular mechanisms involved upstream and downstream of this pathway in order to identify distinct entities that might be manipulated to improve treatment efficacy. Four breast cancer cell lines (T-47D, MCF7, MDA-MB-231 and HBCx-19 established from the eponymous PDX) were treated in vitro with mafosfamide, a DNA damage inducer. In two of these cell lines (MCF7 and HBCx-19), genotoxic treatment upregulated type I IFN expression leading to paracrine activation of IFN/STAT1 signaling pathway after 6-8 days. We show that STING, a well-characterized inducer of IFN in immune cells, is rapidly triggered in MCF7 cells under genotoxic stress and forms nuclear foci that co-localize with phosphorylated IRF-3 and γH2AX. STING silencing abrogated chemotherapy-induced type I IFN production and signaling and potentiated genotoxic treatment efficacy as it promoted cell death extent and delayed cell colony regrowth. Similar results were obtained after silencing PARP12, one selected gene of the IFN/STAT1 pathway fingerprint. In summary, this study provides the first demonstration of STING activation in breast cancer cells. Our data suggest that genotoxic-induced, STING-mediated type I IFN signaling is a cell-intrinsic mechanism of breast cancer cell survival and regrowth.
authors: Inserm, U1151, Institut Necker Enfants Malades (INEM), University Paris Descartes, Faculty of Medicine, Paris, France.|XenTech, 91000 Evry, France.
authors: Julie
authors: J
authors: Gaston
authors: Inserm, U1151, Institut Necker Enfants Malades (INEM), University Paris Descartes, Faculty of Medicine, Paris, France.|XenTech, 91000 Evry, France.
authors: Laura
authors: L
authors: Cheradame
authors: XenTech, 91000 Evry, France.
authors: Vanessa
authors: V
authors: Yvonnet
authors: XenTech, 91000 Evry, France.
authors: Olivier
authors: O
authors: Deas
authors: XenTech, 91000 Evry, France.
authors: Marie-France
authors: MF
authors: Poupon
authors: XenTech, 91000 Evry, France.
authors: Jean-Gabriel
authors: JG
authors: Judde
authors: XenTech, 91000 Evry, France.|LTTA Center, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Italy.
authors: Stefano
authors: S
authors: Cairo
authors: Inserm, U1151, Institut Necker Enfants Malades (INEM), University Paris Descartes, Faculty of Medicine, Paris, France.
authors: Vincent
authors: V
authors: Goffin
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007372:Interferons / Q000378:metabolism; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics*; D019899:Paracrine Communication / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D000099197:STING Protein
chemical_list: D003520:Cyclophosphamide; D007372:Interferons; D008565:Membrane Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C048341:mafosfamide
keywords: PARP12; STAT1; interferon; recurrence