高危子宫内膜癌预后差且发病率逐渐增加。然而，对于驱动该疾病的分子机制的理解仍然有限。我们使用基因工程小鼠模型（GEMM）来确定Fbxw7、Pten和Tp53中的错义突变和功能丧失突变的功能后果，这些基因在近90％的高危子宫内膜癌中都有发生。我们展示了Trp53的删除和错义突变导致不同的表型，其中后者显著促进了子宫内膜癌的发生。我们还展示了Fbxw7错义突变本身并不会导致子宫内膜增生，但能够强烈加速Pten缺失或Trp53错义突变引起的癌变。通过转录组分析，我们发现在Fbxw7/FBXW7突变小鼠和人类子宫内膜癌中，LEF1信号传导上调，同样在携带FBXW7突变的人类等基因细胞系中也是如此，并验证了LEF1和Wnt途径附效子TCF7L2作为新的FBXW7底物。我们的研究为高危子宫内膜癌的生物学提供了新的见解，并暗示LEF1的靶向可能值得在这种治疗抵抗亚组中进行研究探索。© 2023 The Authors. 根据CC BY 4.0许可协议发布。

High-risk endometrial cancer has poor prognosis and is increasing in incidence. However, understanding of the molecular mechanisms which drive this disease is limited. We used genetically engineered mouse models (GEMM) to determine the functional consequences of missense and loss of function mutations in Fbxw7, Pten and Tp53, which collectively occur in nearly 90% of high-risk endometrial cancers. We show that Trp53 deletion and missense mutation cause different phenotypes, with the latter a substantially stronger driver of endometrial carcinogenesis. We also show that Fbxw7 missense mutation does not cause endometrial neoplasia on its own, but potently accelerates carcinogenesis caused by Pten loss or Trp53 missense mutation. By transcriptomic analysis, we identify LEF1 signalling as upregulated in Fbxw7/FBXW7-mutant mouse and human endometrial cancers, and in human isogenic cell lines carrying FBXW7 mutation, and validate LEF1 and the additional Wnt pathway effector TCF7L2 as novel FBXW7 substrates. Our study provides new insights into the biology of high-risk endometrial cancer and suggests that targeting LEF1 may be worthy of investigation in this treatment-resistant cancer subgroup.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.