Abstract：
OBJECTIVE: This study aims to find whether the proliferation and migration of triple negative breast cancer (TNBC) cell lines can be reduced by treatment with bromodomain and extra-terminal domain (BET) inhibitor JQ1 and BET protein targeting chimeras (PROTACs) ARV-771 and MZ1.
METHODS: Cytotoxicity tests, scratch migration assays and western blot proteome profiler arrays for protein expression of cancer-related proteins were used to evaluate the impact of a BET-inhibitor and two BET-directed PROTACs on cell viability, migration and on protein expression.
RESULTS: JQ1 and the PROTACs MZ1 and ARV-771 significantly inhibited the growth and migration of the KRAS G13D-mutated MDA-MB-231 cells. In this cell line, the PROTACs suppressed the residual expression of ERBB2/HER2, 3 and 4 that are essential for the proliferation of breast cancer cells and this cell line proved sensitive to HER2 inhibitors. In contrast, the effects of the PROTACs on the protein expression of MDA-MB-436 cells mostly affected cytokines and their cognate receptors.
CONCLUSIONS: The degradation of BET-protein by PROTACs demonstrated significant anti-proliferative effects. The KRAS-mutated MDA-MB-231 cells belong to the low-HER2 expressing tumors that have a poorer prognosis compared to HER2-null patients. Since first oral PROTACs against tumor hormone receptors are in clinical trials, this mode of tumor therapy is expected to become an important therapeutic strategy in the future treatment of TNBC.
METHODS: Cytotoxicity tests, scratch migration assays and western blot proteome profiler arrays for protein expression of cancer-related proteins were used to evaluate the impact of a BET-inhibitor and two BET-directed PROTACs on cell viability, migration and on protein expression.
RESULTS: JQ1 and the PROTACs MZ1 and ARV-771 significantly inhibited the growth and migration of the KRAS G13D-mutated MDA-MB-231 cells. In this cell line, the PROTACs suppressed the residual expression of ERBB2/HER2, 3 and 4 that are essential for the proliferation of breast cancer cells and this cell line proved sensitive to HER2 inhibitors. In contrast, the effects of the PROTACs on the protein expression of MDA-MB-436 cells mostly affected cytokines and their cognate receptors.
CONCLUSIONS: The degradation of BET-protein by PROTACs demonstrated significant anti-proliferative effects. The KRAS-mutated MDA-MB-231 cells belong to the low-HER2 expressing tumors that have a poorer prognosis compared to HER2-null patients. Since first oral PROTACs against tumor hormone receptors are in clinical trials, this mode of tumor therapy is expected to become an important therapeutic strategy in the future treatment of TNBC.
摘要：
目的：本研究旨在发现三阴性乳腺癌（TNBC）细胞系的增殖和迁移是否可以通过布罗莫结构域和末端外结构域（BET）抑制剂JQ1和BET蛋白靶向嵌合体（PROTACs）ARV-771和MZ1治疗来降低。
方法：细胞毒性试验，用于癌症相关蛋白蛋白表达的划痕迁移测定和蛋白质印迹蛋白质组分析器阵列用于评估BET抑制剂和两种BET定向PROTACs对细胞活力的影响。迁移和蛋白质表达。
结果：JQ1和PROTACsMZ1和ARV-771显著抑制KRASG13D突变的MDA-MB-231细胞的生长和迁移。在这个细胞系中，PROTACs抑制了ERBB2/HER2,3和4的残留表达,这对乳腺癌细胞的增殖至关重要,并且该细胞系被证明对HER2抑制剂敏感.相比之下,PROTACs对MDA-MB-436细胞蛋白质表达的影响主要影响细胞因子及其同源受体。
结论:通过PROTACs降解BET蛋白表现出显著的抗增殖作用。KRAS突变的MDA-MB-231细胞属于低HER2表达肿瘤,其与无HER2患者相比具有较差的预后。由于第一个口服抗肿瘤激素受体的PROTACs正在临床试验中，这种肿瘤治疗模式有望成为未来TNBC治疗的重要治疗策略。
方法：细胞毒性试验，用于癌症相关蛋白蛋白表达的划痕迁移测定和蛋白质印迹蛋白质组分析器阵列用于评估BET抑制剂和两种BET定向PROTACs对细胞活力的影响。迁移和蛋白质表达。
结果：JQ1和PROTACsMZ1和ARV-771显著抑制KRASG13D突变的MDA-MB-231细胞的生长和迁移。在这个细胞系中，PROTACs抑制了ERBB2/HER2,3和4的残留表达,这对乳腺癌细胞的增殖至关重要,并且该细胞系被证明对HER2抑制剂敏感.相比之下,PROTACs对MDA-MB-436细胞蛋白质表达的影响主要影响细胞因子及其同源受体。
结论:通过PROTACs降解BET蛋白表现出显著的抗增殖作用。KRAS突变的MDA-MB-231细胞属于低HER2表达肿瘤,其与无HER2患者相比具有较差的预后。由于第一个口服抗肿瘤激素受体的PROTACs正在临床试验中，这种肿瘤治疗模式有望成为未来TNBC治疗的重要治疗策略。
