Activation of IFN/STAT1 signalling predicts response to chemotherapy in oestrogen receptor-negative breast cancer

Abstract

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.

Intracellular STING inactivation sensitizes breast cancer cells to genotoxic agents

“…Using several breast cancer patient-derived xenografts (PDXs), we were recently able to distinguish xenografts which resisted de novo to chemotherapy, and others which initially regressed under treatment, but progressed with constant recurrences [2]. Furthermore, the responses to chemotherapy were tightly related to the activation of IFN/STAT1 signaling in post-treatment residual cancer cells [2].…”

“…Furthermore, the responses to chemotherapy were tightly related to the activation of IFN/STAT1 signaling in post-treatment residual cancer cells [2]. Indeed, the upregulation of an IFN fingerprint covering 140 IFN-stimulated genes (ISGs) was observed in responding tumors only [2]. This IFN-related response was correlated with STAT1 phosphorylation and massive DNA damage, ɣH2AX.…”

“…aGenes selected to represent the diversity of the IFN/STAT1 fingerprint induced in residual tumor cells after chemotherapy in responder PDXs [2]. …”

“…In this context, and following up our recent findings using breast cancer PDXs [2], the present study was designed with the double aim to elucidate i) the molecular mechanisms by which cell-intrinsic IFN signaling was triggered in cancer cells in response to chemotherapy, and ii) the ultimate contribution of the ISG fingerprint to the tumor response to treatment. In order to avoid any interference with biological responses induced by the immune cells present in the tumor microenvironment in vivo , we privileged an in vitro approach.…”

GRIM-19: A master regulator of cytokine induced tumor suppression, metastasis and energy metabolism

“…Nonetheless, the single-agent efficacy of IFNs is comparable to many currently used chemotherapeutics. A number of recent reports indicate that the success of conventional chemotherapeutics, targeted anti-cancer agents, radiotherapy and immunotherapy relies on type-I IFN signaling [9–14] in vivo . As a result, several human cancers accumulate IFN signaling defects to escape from growth suppression [15].…”