乳腺癌（BC）仍然是女性癌症相关死亡的第二大原因。对雌激素受体 (ER) 抑制剂他莫昔芬等激素疗法的耐药性是 BC 治疗的主要障碍。 zeste 同源物 2 (EZH2) 的增强子是 Polycomb 抑制复合物 2 (PRC2) 的甲基转移酶成分，与他莫昔芬耐药有关。有证据表明，EZH2 通常以不依赖甲基转移酶的方式通过与致癌转录因子相互作用而作为转录共激活因子发挥非经典功能。与甲基转移酶抑制剂不同，蛋白水解靶向嵌合体 (PROTAC) 可以抑制 EZH2 的激活和抑制功能。在这里，我们发现，与甲基转移酶抑制剂相比，EZH2 PROTAC、MS177 和 MS8815 能更大程度地有效抑制 BC 细胞（包括具有获得性他莫昔芬耐药性的细胞）的生长。从机制上讲，EZH2 与叉头框 M1 (FOXM1) 结合，并与 FOXM1 靶基因的启动子结合。 EZH2 PROTAC 诱导 EZH2 和 FOXM1 降解，导致参与细胞周期进程和他莫昔芬耐药性的靶基因表达减少。总之，这项研究支持 EZH2 靶向 PROTAC 代表了 BC 未来治疗的一个有前途的研究途径，包括在他莫昔芬耐药的情况下。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Breast cancer (BC) remains the second leading cause of cancer-related mortalities in women. Resistance to hormone therapies such as tamoxifen, an estrogen receptor (ER) inhibitor, is a major hurdle in the treatment of BC. Enhancer of zeste homolog 2 (EZH2), the methyltransferase component of the Polycomb repressive complex 2 (PRC2), has been implicated in tamoxifen resistance. Evidence suggests that EZH2 often functions noncanonically, in a methyltransferase-independent manner, as a transcription coactivator through interacting with oncogenic transcription factors. Unlike methyltransferase inhibitors, proteolysis targeting chimeras (PROTAC) can suppress both activating and repressive functions of EZH2. Here, we find that EZH2 PROTACs, MS177 and MS8815, effectively inhibited the growth of BC cells, including those with acquired tamoxifen resistance, to a much greater degree when compared to methyltransferase inhibitors. Mechanistically, EZH2 associates with forkhead box M1 (FOXM1) and binds to the promoters of FOXM1 target genes. EZH2 PROTACs induce degradation of both EZH2 and FOXM1, leading to reduced expression of target genes involved in cell cycle progression and tamoxifen resistance. Together, this study supports that EZH2-targeted PROTACs represent a promising avenue of research for the future treatment of BC, including in the setting of tamoxifen resistance.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.