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.
Highlights
Chemotherapy is active in numerous cancers, reducing tumor growth and lengthening patient survival
Preliminary screening of various breast cancer cell models identified MCF7, T-47D and MDA-MB-231 cell lines and HBCx-19, a primary cell line derived from the eponymous patient-derived xenografts (PDXs), as those exhibiting the most robust molecular responses to genotoxic stress
The genotoxic stress triggers IFN production in breast cancer cells which respond to chemotherapy and not in de novo resistant tumors, irrespectively of their hormone receptor status and p53 mutated type
Summary
Chemotherapy is active in numerous cancers, reducing tumor growth and lengthening patient survival. These benefits are not constant and frequently transient, reflecting the ability of cancer cells to survive to drug toxicity. Resistance to chemotherapy can be observed de novo, as identified by the lack of tumor response. Escape to treatment can occur after an initial response, defining a process of drug-resistance differing from the de novo resistance. Such an adaptive survival is frequent and responsible for tumor recurrences after response to chemotherapy. Improving the efficacy of treatment by prevention of cancer cell survival and recurrence is currently an active area of research [1] and of rational hope
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