RESUMEN
BACKGROUND: Oestrogen receptor-negative (ER-) breast cancer is intrinsically sensitive to chemotherapy. However, tumour response is often incomplete, and relapse occurs with high frequency. The aim of this work was to analyse the molecular characteristics of residual tumours and early response to chemotherapy in patient-derived xenografts (PDXs) of breast cancer. METHODS: Gene and protein expression profiles were analysed in a panel of ER- breast cancer PDXs before and after chemotherapy treatment. Tumour and stromal interferon-gamma expression was measured in xenografts lysates by human and mouse cytokine arrays, respectively. RESULTS: The analysis of residual tumour cells in chemo-responder PDX revealed a strong overexpression of IFN-inducible genes, induced early after AC treatment and associated with increased STAT1 phosphorylation, DNA-damage and apoptosis. No increase in IFN-inducible gene expression was observed in chemo-resistant PDXs upon chemotherapy. Overexpression of IFN-related genes was associated with human IFN-γ secretion by tumour cells. CONCLUSIONS: Treatment-induced activation of the IFN/STAT1 pathway in tumour cells is associated with chemotherapy response in ER- breast cancer. Further validations in prospective clinical trials will aim to evaluate the usefulness of this signature to assist therapeutic strategies in the clinical setting.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica , Interferón gamma/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Factor de Transcripción STAT1/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales , Animales , Antígenos/efectos de los fármacos , Antígenos/genética , Antígenos/metabolismo , Western Blotting , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Capecitabina/farmacología , Proteínas Portadoras/efectos de los fármacos , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Caspasa 3/efectos de los fármacos , Caspasa 3/genética , Caspasa 3/metabolismo , Caspasa 7/efectos de los fármacos , Caspasa 7/genética , Caspasa 7/metabolismo , Cisplatino/farmacología , Citocinas/efectos de los fármacos , Citocinas/genética , Citocinas/metabolismo , Proteínas del Citoesqueleto/efectos de los fármacos , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Hibridación in Situ , Interferón beta/efectos de los fármacos , Interferón beta/genética , Interferón beta/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Péptidos y Proteínas de Señalización Intracelular/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/efectos de los fármacos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Desnudos , Proteínas Mitocondriales/efectos de los fármacos , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Proteínas de Resistencia a Mixovirus/efectos de los fármacos , Proteínas de Resistencia a Mixovirus/genética , Proteínas de Resistencia a Mixovirus/metabolismo , Trasplante de NeoplasiasRESUMEN
[This corrects the article DOI: 10.18632/oncotarget.12858.].
RESUMEN
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.