Chemotherapy remains the mainstay of treatment for advanced breast cancer; however, resistance is an inevitable event for the majority of patients with metastatic disease. Moreover, there is little information available to guide stratification of first-line chemotherapy, crucial given the common development of multidrug resistance. Here, we describe an in vivo screen to interrogate the response to anthracycline-based chemotherapy in a syngeneic metastatic breast cancer model and identify JNK signaling as a key modulator of chemotherapy response. Combining in vitro and in vivo functional analyses, we demonstrate that JNK inhibition both promotes tumor cell cytostasis and blocks activation of the proapoptotic protein Bax, thereby antagonizing chemotherapy-mediated cytotoxicity. To investigate the clinical relevance of this dual role of JNK signaling, we developed a proliferation-independent JNK activity signature and demonstrate high JNK activity to be enriched in triple-negative and basal-like breast cancer subtypes. Consistent with the dual role of JNK signaling in vitro , high-level JNK pathway activation in triple-negative breast cancers is associated both with poor patient outcome in the absence of chemotherapy treatment and, in neoadjuvant clinical studies, is predictive of enhanced chemotherapy response. These data highlight the potential of monitoring JNK activity as early biomarker of response to chemotherapy and emphasize the importance of rational treatment regimes, particularly when combining cytostatic and chemotherapeutic agents. Mol Cancer Ther; 16(9); 1967–78. ©2017 AACR .

中文翻译：

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体内功能筛查确定JNK信号作为乳腺癌化学治疗反应的调节剂。

化学疗法仍然是晚期乳腺癌的主要治疗手段。然而，对于大多数转移性疾病患者来说，耐药性是不可避免的事件。此外，鉴于多药耐药的共同发展，很少有信息可指导一线化疗的分层。在这里，我们描述了体内筛选，以询问在同基因转移性乳腺癌模型中对基于蒽环类药物的化学疗法的反应，并确定JNK信号传导是化学疗法反应的关键调节剂。结合体外和体内功能分析，我们证明JNK抑制既能促进肿瘤细胞的细胞停滞，又能抑制促凋亡蛋白Bax的活化，从而拮抗化学疗法介导的细胞毒性。为了研究这种JNK信号双重作用的临床意义，我们开发了不依赖增殖的JNK活性标记，并证明了高JNK活性可以丰富三阴性和基底样乳腺癌亚型。与体外JNK信号的双重作用一致，三联阴性乳腺癌中的高水平JNK途径活化与缺乏化疗的患者预后差有关，并且在新辅助临床研究中，预示着化疗反应将增强。这些数据强调了监测JNK活性作为对化学疗法反应的早期生物标志物的潜力，并强调了合理治疗方案的重要性，尤其是在组合细胞抑制药和化学治疗剂时。分子癌疗法；16（9）; 1967–78年。©2017 AACR。