Abstract

Brain metastasis affects approximately 20%–30% of patients with triple-negative breast cancers (TNBCs). Even small metastatic lesions in the brain can trigger severe neurological impairments and result in extremely short survival time. Recently, active astrocytes were reported to be associated with brain metastases. However, how activated astrocytes regulate the behaviors of disseminated breast cancer cells in the brain remains unknown. In this study, human primary astrocytes were stimulated with IL-1β to form active astrocytes to study the cross-talk between stromal cells (astrocytes) and TNBC cells in brain metastases. Our results showed that active astrocytes significantly increase the malignancy of TNBC cells and prevent them from undergoing apoptosis caused by doxorubicin. We also found that the high level of IL-6 secreted by activated astrocytes was responsible for the drug resistance of breast cancer, which could be abolished by treatment of astrocytes with tamoxifen (TAM). The blockage of active astrocyte-derived IL-6 by a neutralizing antibody resulted in the attenuation of drug resistance, consequently enhancing the sensitivity of breast cancer cells to doxorubicin. Furthermore, the possible involved TAM-modulated drug resistance mechanism may be associated with a decrease in IL-6 expression in astrocytes and the downregulation of MAPK and JAK2/STAT3 signaling in cancer cells. Our data suggested that TAMs might reduce drug resistance through the IL-6/JAK2/STAT3 signaling pathway, providing a possible therapy to treat brain metastasis in TNBCs, as estrogen receptor inhibitors (TAMs, etc.) can cross the blood–brain barrier.

中文翻译：

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他莫昔芬通过IL-6 / STAT3信号通路减弱星形胶质细胞反应性脑转移和耐药性

摘要

脑转移会影响三阴性乳腺癌（TNBC）的患者约20％–30％。即使是脑部微小的转移性病变也会触发严重的神经功能损害，并导致极短的生存时间。最近，据报道活跃的星形胶质细胞与脑转移有关。然而，激活的星形胶质细胞如何调节脑中弥散性乳腺癌细胞的行为仍然未知。在这项研究中，用IL-1β刺激人类原代星形胶质细胞形成活性星形胶质细胞，以研究脑转移中基质细胞（星形细胞）和TNBC细胞之间的串扰。我们的结果表明，活跃的星形胶质细胞可显着增加TNBC细胞的恶性程度，并防止其经历由阿霉素引起的凋亡。我们还发现，活化星形胶质细胞分泌的高水平的IL-6导致了乳腺癌的耐药性，这可以通过用他莫昔芬（TAM）治疗星形胶质细胞来消除。中和抗体对星形胶质细胞源性IL-6的阻滞作用导致耐药性降低，从而增强了乳腺癌细胞对阿霉素的敏感性。此外，可能涉及的TAM调节的耐药机制可能与星形胶质细胞中IL-6表达的降低以及癌细胞中MAPK和JAK2 / STAT3信号的下调有关。我们的数据表明，TAMs可能通过IL-6 / JAK2 / STAT3信号通路降低耐药性，提供了可能的疗法来治疗TNBCs中的脑转移，如雌激素受体抑制剂（TAMs等）。