通过组蛋白翻译后修饰对基因表达的调控在乳腺癌发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仍不清楚。为了更深入了解组蛋白修饰酶Enhancer of Zeste homology 2 (Ezh2) 在乳腺瘤早期阶段中的作用，我们使用了诱导性乳腺器官样体系，这个体系带有条件性Ezh2等位基因，能够忠实地重现腺泡B型乳腺癌起始的关键事件。我们显示，Ezh2的丢失严重影响致癌基因诱导的器官样体系的生长，且Ezh2缺失的器官样体系维持极性上皮细胞表型。转录组学分析显示，Ezh2缺失的乳腺上皮细胞上调了Wnt信号的负调控因子的表达，并且下调了参与 mTORC1 (rapamycin靶向机制靶标-1复合物)信号传导的基因的表达。我们确定了Sfrp1，一个Wnt信号抑制因子，作为Ezh2的靶基因，它在Ezh2缺失的上皮组织中被解抑并且表达。此外，对乳腺癌数据的分析显示，Sfrp1表达与腺泡B型乳腺癌患者的良好临床结果相关。最后，我们确认了通过间接机制上调肿瘤抑制因子Pten的表达，Ezh2的靶向治疗影响了mTORC1的活性。这些发现表明，Ezh2在乳腺瘤早期阶段整合了mTORC1和Wnt信号通路，认为抑制Ezh2或以治疗为目标的Ezh2依赖性程序对早期腺泡B型乳腺癌的治疗可能是有益的。

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 Ezh2 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 Sfrp1, 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 Sfrp1 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.