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：

---

体内功能筛选将 JNK 信号识别为乳腺癌化疗反应的调节剂

化疗仍然是晚期乳腺癌的主要治疗方法。然而，对于大多数转移性疾病患者来说，耐药是不可避免的。此外，可用于指导一线化疗分层的信息很少，鉴于多药耐药的共同发展，这一点至关重要。在这里，我们描述了一种体内筛选，以在同基因转移性乳腺癌模型中询问对蒽环类化疗的反应，并将 JNK 信号确定为化疗反应的关键调节剂。结合体外和体内功能分析，我们证明 JNK 抑制既促进肿瘤细胞细胞停滞，又阻止促凋亡蛋白 Bax 的激活，从而拮抗化疗介导的细胞毒性。为了研究 JNK 信号的这种双重作用的临床相关性，我们开发了一种不依赖增殖的 JNK 活性特征，并证明了在三阴性和基底样乳腺癌亚型中富集的高 JNK 活性。与体外 JNK 信号传导的双重作用一致，三阴性乳腺癌中的高水平 JNK 通路激活与没有化疗治疗的患者预后不良有关，并且在新辅助临床研究中，可预测化疗反应增强。这些数据突出了监测 JNK 活性作为对化疗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，特别是在结合细胞抑制剂和化疗药物时。摩尔癌症治疗; 16(9); 1967-78。©2017 AACR。