| Summary: | 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 <i>Fbxw7</i>, <i>Pten</i> and <i>Tp53</i>, which collectively occur in nearly 90% of high-risk endometrial cancers. We show that <i>Trp53</i> deletion and missense mutation cause different phenotypes, with the latter a substantially stronger driver of endometrial carcinogenesis. We also show that <i>Fbxw7</i> missense mutation does not cause endometrial neoplasia on its own, but potently accelerates carcinogenesis caused by <i>Pten</i> loss or <i>Trp53</i> missense mutation. By transcriptomic analysis, we identify LEF1 signalling as upregulated in <i>Fbxw7/FBXW7</i>-mutant mouse and human endometrial cancers, and in human isogenic cell lines carrying <i>FBXW7</i> mutation, and validate LEF1 and the additional Wnt pathway effector TCF7L2 as novel <i>FBXW7</i> 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.
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