溴结构域和额外终端（BET）蛋白被认为是乙酰化组蛋白H4赖氨酸的识别因子，并作为骨架蛋白，将许多其他蛋白质招募到活跃基因的启动子和增强子中，特别是在关键基因的超增强子中，推动转录过程，并被确定为乳腺癌潜在治疗靶点。然而，BET抑制剂如JQ1在乳腺癌治疗中的疗效受到白细胞介素-6（IL-6）的干扰，具体机制尚未确定。我们研究了IL-6和JQ1在MCF-7和MDA-MB-231人乳腺癌细胞中的相互作用。结果表明，JQ1对细胞生长和凋亡的抑制作用在MDA-MB-231细胞中比在MCF-7细胞中更强。此外，MCF-7细胞在IL-6处理后表现出CXCR4的表达增加，而MDA-MB-231细胞则没有。JQ1显著降低了两种细胞系中的CXCR4表面表达，并减弱了JQ1对MCF-7细胞的IL-6预处理效果。虽然IL-6抑制了MCF-7细胞中乳腺癌干细胞的扩展，但JQ1阻碍了其抑制作用。在MCF-7细胞中，JQ1按时间依赖性增加了老化细胞的数量。基因表达分析表明，JQ1和IL-6在MCF-7细胞中协同增加了SNAIL的表达，并降低了c-MYC的表达。因此，BET蛋白是晚期乳腺癌中有希望的新型靶点。类似于JQ1的BET抑制剂在乳腺癌中显示出治疗潜力，特别是当三阴性乳腺癌细胞增加和/或存在肿瘤促进因子如IL-6在肿瘤微环境中时。© 2023. 本文作者授权给Springer Nature B.V.。

Bromodomain and extra-terminal (BET) proteins are recognized acetylated lysine of histone 4 and act as scaffolds to recruit many other proteins to promoters and enhancers of active genes, especially at the super-enhancers of key genes, driving the transcription process and have been identified as potential therapeutic targets in breast cancer. However, the efficacy of BET inhibitors such as JQ1 in breast cancer therapy is impeded by interleukin-6 (IL-6) through an as-yet-defined mechanism.We investigated the interplay between IL-6 and JQ1 in MCF-7 and MDA-MB-231 human breast cancer cells. The results demonstrate that the efficacy of JQ1 on the inhibition of cell growth and apoptosis was stronger in MDA-MB-231 cells than in MCF-7 cells. Further, MCF-7 cells, but not MDA-MB-231 cells, exhibited increased expression of CXCR4 following IL-6 treatment. JQ1 significantly reduced CXCR4 surface expression in both cell lines and diminished the effects of IL-6 pre-treatment on MCF-7 cells. While IL-6 suppressed the extension of breast cancer stem cells in MCF-7 cells, JQ1 impeded its inhibitory effect. In MCF-7 cells JQ1 increased the number of senescent cells in a time-dependent manner.Analysis of gene expression indicated that JQ1 and IL-6 synergistically increase SNAIL expression and decrease c-MYC expression in MCF-7 cells. So, the BET proteins are promising, novel therapeutic targets in late-stage breast cancers. BET inhibitors similar to JQ1 show promise as therapeutic candidates for breast cancers, especially when triple-negative breast cancer cells are increased and/or tumor-promoting factors like IL-6 exist in the tumor microenvironment.© 2023. The Author(s), under exclusive licence to Springer Nature B.V.