Macrophages confer resistance to BET inhibition in triple-negative breast cancer by upregulating IKBKE.
Macrophages confer resistance to BET inhibition in triple-negative breast cancer by upregulating IKBKE.
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巨噬细胞通过上调 IKBKE 赋予三阴性乳腺癌对 BET 抑制的抵抗力。
DOI：
10.1016/j.bcp.2020.114126
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发表时间：
2020-06
影响因子：
5.8
通讯作者：
Zhengzhi Zou
中科院分区：
文献类型：
--
作者：
Jianghua Qiao;Yibing Chen;Yanjun Mi;Huan Jin;Ting Huang;Haolong Li;Qiming Wang;Yucen Song;Baoyan Wu;Lina Wang;Jun Cao;Zhengzhi Zou
BET抑制剂（BETi）在三阴性乳腺癌（TNBC）中表现出较强的抗肿瘤活性。然而，在TNBC中已经报道了BETi抗性。耐药机制尚未得到证实。肿瘤相关巨噬细胞（TAM）经常参与癌细胞对化疗的耐药性，也与TNBC的不良预后相关。然而，TAM在BETi抗性中的作用仍然未知。在此，我们发现BETi JQ 1和I-BET 151通过降低IKBKE表达以减弱NF-κB信号传导而在TNBC中发挥抗肿瘤作用。据报道，TAM与乳腺癌的化疗耐药性有关。在此，我们首次发现TNBC刺激的TAMs通过上调IKBKE表达激活NF-κB信号，从而增强乳腺癌细胞对BETi的抗性。还证明临床TNBC组织中的IKBKE水平高于非TNBC组织，表明TNBC中TNBC刺激的TAM对IKBKE表达的反馈诱导。此外，TNBC细胞中TAM对IKBKE的诱导被鉴定为与STAT 3信号传导相关，STAT 3信号传导由TAM分泌的IL-6和IL-10激活。BET抑制剂与STAT 3抑制剂联合应用对TAM共培养或TAM CM处理的TNBC细胞在体外和体内均表现出协同抑制作用。总之，我们的发现说明TNBC活化的巨噬细胞通过IL-6或IL-10/STAT 3/IKBKE/NF-κB轴赋予TNBC细胞对BETi的抗性。阻断IKBKE或双重抑制BET和STAT 3可能是治疗TNBC的新策略。
BET inhibitors (BETi) exhibit a strong anti-tumor activity in triple-negative breast cancer (TNBC). However, BETi resistance has been reported in TNBC. The mechanisms of resistance have not been demonstrated. Tumor-associated macrophages (TAMs) are frequently involved in cancer cells resistance to chemotherapy, also associated with poor prognosis in TNBC. However, the role of TAMs in BETi resistance remains unknown. Here, we found that BETi JQ1 and I-BET151 exerted anti-tumor effects in TNBC by decreasing IKBKE expression to attenuate NF-κB signaling. TAMs have been reported to associate with chemoresistance in breast cancer. Here, we firstly found that TNBC-stimulated TAMs activated NF-κB signaling by upregulating IKBKE expression to enhance breast cancer cells resistance to BETi. The IKBKE levels were also proved to be higher in clinical TNBC tissues than Non-TNBC tissues, suggesting feedback induction of IKBKE expression by TNBC-stimulated TAMs in TNBC. Moreover, the induction of IKBKE by TAMs in TNBC cells was identified to be associated with STAT3 signaling, which was activated by TAM-secreted IL-6 and IL-10. Lastly, the combination of inhibitors of BET and STAT3 exerted a synergistic inhibition effects in TAM-cocultured or TAM CM-treated TNBC cellsin vitroandin vivo. Altogether, our findings illustrated TNBC-activated macrophages conferred TNBC cells resistance to BETi via IL-6 or IL-10/STAT3/IKBKE/NF-κB axis. Blockade of IKBKE or double inhibition of BET and STAT3 might be a novel strategy for treatment of TNBC.
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