Rosalind and Morris Goodman Cancer Research Institute, McGill University, Montreal, QC H3A 1A3, Canada.
Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
Proc Natl Acad Sci U S A. 2023 Aug 15;120(33):e2303010120. doi: 10.1073/pnas.2303010120. Epub 2023 Aug 7.
The regulation of gene expression through histone posttranslational modifications plays a crucial role in breast cancer progression. However, the molecular mechanisms underlying the contribution of histone modification to tumor initiation remain unclear. To gain a deeper understanding of the role of the histone modifier Enhancer of Zeste homology 2 (Ezh2) in the early stages of mammary tumor progression, we employed an inducible mammary organoid system bearing conditional alleles that faithfully recapitulates key events of luminal B breast cancer initiation. We showed that the loss of Ezh2 severely impairs oncogene-induced organoid growth, with Ezh2-deficient organoids maintaining a polarized epithelial phenotype. Transcriptomic profiling showed that Ezh2-deficient mammary epithelial cells up-regulated the expression of negative regulators of Wnt signaling and down-regulated genes involved in mTORC1 (mechanistic target of rapamycin complex 1) signaling. We identified , a Wnt signaling suppressor, as an Ezh2 target gene that is derepressed and expressed in Ezh2-deficient epithelium. Furthermore, an analysis of breast cancer data revealed that expression was associated with favorable clinical outcomes in luminal B breast cancer patients. Finally, we confirmed that targeting Ezh2 impairs mTORC1 activity through an indirect mechanism that up-regulates the expression of the tumor suppressor Pten. These findings indicate that Ezh2 integrates the mTORC1 and Wnt signaling pathways during early mammary tumor progression, arguing that inhibiting Ezh2 or therapeutically targeting Ezh2-dependent programs could be beneficial for the treatment of early-stage luminal B breast cancer.
通过组蛋白翻译后修饰来调节基因表达在乳腺癌进展中起着至关重要的作用。然而，组蛋白修饰对肿瘤起始的贡献的分子机制尚不清楚。为了更深入地了解组蛋白修饰剂 Enhancer of Zeste homology 2 (Ezh2) 在乳腺肿瘤早期进展中的作用，我们采用了一种诱导型乳腺类器官系统，该系统携带条件性 等位基因，忠实地再现了腔 B 型乳腺癌起始的关键事件。我们表明，Ezh2 的缺失严重损害了致癌基因诱导的类器官生长，Ezh2 缺陷的类器官保持极化的上皮表型。转录组谱分析表明，Ezh2 缺陷的乳腺上皮细胞上调了 Wnt 信号的负调节剂的表达，并下调了参与 mTORC1（雷帕霉素复合物 1 的机械靶标）信号的基因。我们确定了作为 Ezh2 的靶基因，它在 Ezh2 缺陷的上皮细胞中被解除抑制并表达。此外，对乳腺癌数据的分析表明，在腔 B 型乳腺癌患者中， 的表达与良好的临床结局相关。最后，我们证实靶向 Ezh2 通过间接机制抑制 mTORC1 活性，该机制上调肿瘤抑制因子 Pten 的表达。这些发现表明，Ezh2 在早期乳腺肿瘤进展过程中整合了 mTORC1 和 Wnt 信号通路，这表明抑制 Ezh2 或治疗性靶向 Ezh2 依赖性程序可能有益于治疗早期腔 B 型乳腺癌。
