BET inhibition increases βIII-tubulin expression and sensitizes metastatic breast cancer in the brain to vinorelbine.
BET inhibition increases βIII-tubulin expression and sensitizes metastatic breast cancer in the brain to vinorelbine.
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DOI：
10.1126/scitranslmed.aax2879
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发表时间：
2020-08-26
影响因子：
17.1
通讯作者：
Lesniak MS
中科院分区：
文献类型：
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作者：
Kanojia D;Panek WK;Cordero A;Fares J;Xiao A;Savchuk S;Kumar K;Xiao T;Pituch KC;Miska J;Zhang P;Kam KL;Horbinski C;Balyasnikova IV;Ahmed AU;Lesniak MS
原发性乳腺癌转移导致生存率低。 βIII-微管蛋白（TUBB3）已被确定为乳腺癌脑转移的治疗靶点。在这项研究中，我们进行了系统分析，以确定乳腺癌脑转移中 TUBB3 表达的调节，并使用美国食品和药物管理局 (FDA) 批准的药物长春瑞滨 (VRB) 策略性地靶向这些转移。我们发现人表皮生长因子受体 2 (HER2) 信号传导可调节曲妥珠单抗敏感和曲妥珠单抗耐药肿瘤细胞中的 TUBB3 表达。我们进一步发现溴结构域和额外末端结构域 (BET) 抑制会增加 TUBB3 的表达，使肿瘤细胞更容易受到 VRB 的凋亡影响。使用两种不同乳腺癌细胞模型的原位异种移植试验显示，BET 抑制和 VRB 治疗可减少肿瘤体积。此外，使用多发性脑转移 (BM) 模型的体内研究表明，放射 + BET 抑制剂 (iBET-762) + VRB 组合可提高生存率（75% 长期生存者，P < 0.05）。使用计算机分析和 BET 抑制，我们发现转录因子髓样锌指-1 (MZF-1) 蛋白与 TUBB3 启动子结合。 BET 抑制会降低 MZF-1 表达，随后增加 TUBB3 表达。 MZF-1 的过表达会降低体内 TUBB3 的表达并减少 BM，而其敲低则会增加乳腺癌细胞中 TUBB3 的表达。总之，本研究证明了 TUBB3 的调节机制，并为应用 BET 抑制使乳腺癌转移对 VRB 介导的治疗敏感提供了支持。
Metastases from primary breast cancer result in poor survival. βIII-tubulin (TUBB3) has been established as a therapeutic target for breast cancer metastases specifically to the brain. In this study, we conducted a systematic analysis to determine the regulation of TUBB3 expression in breast cancer metastases to the brain and strategically target these metastases using vinorelbine (VRB), a drug approved by the U.S. Food and Drug Administration (FDA). We found that human epidermal growth factor receptor 2 (HER2) signaling regulates TUBB3 expression in both trastuzumab-sensitive and trastuzumab-resistant neoplastic cells. We further discovered that bromodomain and extra-terminal domain (BET) inhibition increases TUBB3 expression, rendering neoplastic cells more susceptible to apoptosis by VRB. Orthotopic xenograft assays using two different breast cancer cell models revealed a reduction in tumor volume with BET inhibition and VRB treatment. In addition, in vivo studies using a model of multiple brain metastasis (BM) showed improved survival with the combination of radiation + BET inhibitor (iBET-762) + VRB (75% long-term survivors, P < 0.05). Using in silico analysis and BET inhibition, we found that the transcription factor myeloid zinc finger-1 (MZF-1) protein binds to the TUBB3 promoter. BET inhibition decreases MZF-1 expression and subsequently increases TUBB3 expression. Overexpression of MZF-1 decreases TUBB3 expression and reduces BM in vivo, whereas its knockdown increases TUBB3 expression in breast cancer cells. In summary, this study demonstrates a regulatory mechanism of TUBB3 and provides support for an application of BET inhibition to sensitize breast cancer metastases to VRB-mediated therapy.