Research Papers:

This article has been corrected. Correction in: Oncotarget. 2019; 10:4249-4251.

Intracellular STING inactivation sensitizes breast cancer cells to genotoxic agents

Julie Gaston, Laura Cheradame, Vanessa Yvonnet, Olivier Deas, Marie-France Poupon, Jean-Gabriel Judde, Stefano Cairo and Vincent Goffin _

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Oncotarget. 2016; 7:77205-77224. https://doi.org/10.18632/oncotarget.12858

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Julie Gaston1,2, Laura Cheradame1,2, Vanessa Yvonnet2, Olivier Deas2, Marie-France Poupon2, Jean-Gabriel Judde2, Stefano Cairo2,3,*, Vincent Goffin1,*

1Inserm, U1151, Institut Necker Enfants Malades (INEM), University Paris Descartes, Faculty of Medicine, Paris, France

2XenTech, 4 rue Pierre Fontaine, 91000 Evry, France

3LTTA Center, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Italy

*These authors contributed equally to this work

Correspondence to:

Vincent Goffin, email: [email protected]

Keywords: interferon, STAT1, PARP12, recurrence

Received: April 25, 2016     Accepted: October 17, 2016     Published: October 24, 2016


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.

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