Triple-negative breast cancer (TNBC) often develops resistance to single-agent treatment, which can be circumvented using targeted combinatorial approaches. Here, we demonstrate that the simultaneous inhibition of LOXL2 and BRD4 synergistically limits TNBC proliferation in vitro and in vivo. Mechanistically, LOXL2 interacts in the nucleus with the short isoform of BRD4 (BRD4S), MED1, and the cell cycle transcriptional regulator B-MyB. These interactions sustain the formation of BRD4 and MED1 nuclear transcriptional foci and control cell cycle progression at the gene expression level. The pharmacological co-inhibition of LOXL2 and BRD4 reduces BRD4 nuclear foci, BRD4-MED1 colocalization, and the transcription of cell cycle genes, thus suppressing TNBC cell proliferation. Targeting the interaction between BRD4S and LOXL2 could be a starting point for the development of new anticancer strategies for the treatment of TNBC.

中文翻译：

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BRD4S、LOXL2 和 MED1 之间的相互作用驱动三阴性乳腺癌细胞周期转录


三阴性乳腺癌 (TNBC) 通常会对单药治疗产生耐药性，可以使用有针对性的组合方法来规避这种耐药性。在这里，我们证明同时抑制 LOXL2 和 BRD4 可协同限制体外和体内TNBC 增殖。从机制上讲，LOXL2 在细胞核中与 BRD4 (BRD4S) 的短亚型、MED1 和细胞周期转录调节因子 B-MyB 相互作用。这些相互作用维持 BRD4 和 MED1 核转录灶的形成，并在基因表达水平上控制细胞周期进程。 LOXL2 和 BRD4 的药理学共同抑制可减少 BRD4 核灶、BRD4-MED1 共定位以及细胞周期基因的转录，从而抑制 TNBC 细胞增殖。针对 BRD4S 和 LOXL2 之间的相互作用可能是开发治疗 TNBC 的新抗癌策略的起点。