Functional analysis reveals driver cooperativity and novel mechanisms in endometrial carcinogenesis

AbstractHigh‐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 inFbxw7,PtenandTp53, which collectively occur in nearly 90% of high‐risk endometrial cancers. We show thatTrp53deletion and missense mutation cause different phenotypes, with the latter a substantially stronger driver of endometrial carcinogenesis. We also show thatFbxw7missense mutation does not cause endometrial neoplasia on its own, but potently accelerates carcinogenesis caused byPtenloss orTrp53missense mutation. By transcriptomic analysis, we identify LEF1 signalling as upregulated inFbxw7/FBXW7‐mutant mouse and human endometrial cancers, and in human isogenic cell lines carryingFBXW7mutation, 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.