Activation of IFN/STAT1 signalling predicts response to chemotherapy in oestrogen receptor-negative breast cancer.
Activation of IFN/STAT1 signalling predicts response to chemotherapy in oestrogen receptor-negative breast cancer.
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DOI：
10.1038/bjc.2015.398
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发表时间：
2016-01-19
影响因子：
8.8
通讯作者：
Marangoni E
中科院分区：
文献类型：
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作者：
Legrier ME;Bièche I;Gaston J;Beurdeley A;Yvonnet V;Déas O;Thuleau A;Château-Joubert S;Servely JL;Vacher S;Lassalle M;Depil S;Tucker GC;Fontaine JJ;Poupon MF;Roman-Roman S;Judde JG;Decaudin D;Cairo S;Marangoni E
雌激素受体阴性（ER−）乳腺癌本质上对化疗敏感。然而，肿瘤反应往往不完全，并且复发率很高。这项工作的目的是分析乳腺癌患者来源的异种移植物（PDX）中残留肿瘤的分子特征和对化疗的早期反应。在化疗之前和之后对一组 ER− 乳腺癌 PDX 的基因和蛋白质表达谱进行了分析。分别通过人和小鼠细胞因子阵列测量异种移植物裂解物中的肿瘤和基质干扰素-γ表达。对化学反应 PDX 中残留肿瘤细胞的分析揭示了 IFN 诱导基因的强烈过度表达，这种基因在 AC 治疗后早期诱导，并与 STAT1 磷酸化、DNA 损伤和细胞凋亡增加相关。化疗后，化疗耐药的 PDX 中未观察到 IFN 诱导基因表达增加。 IFN相关基因的过度表达与肿瘤细胞分泌人IFN-γ有关。治疗诱导的肿瘤细胞中 IFN/STAT1 通路的激活与 ER− 乳腺癌的化疗反应相关。前瞻性临床试验中的进一步验证将旨在评估该特征在临床环境中协助治疗策略的有用性。
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. 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. 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. 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.