Functional Analysis Reveals Driver Cooperativity and Novel Mechanisms in Endometrial Carcinogenesis

Authors

Matthew Brown
Alicia Leon
Katarzyna Kedzierska
Charlotte Moore
Hayley L Belnoue-Davis
Susanne Flach
John P Lydon
Francesco J DeMayo
Annabelle Lewis
Tjalling Bosse
Ian Tomlinson
David N Church

Publication Date

10-11-2023

Journal

EMBO Molecular Medicine

DOI

10.15252/emmm.202217094

PMID

37589076

PMCID

PMC10565641

Published Open-Access

no

Keywords

Female, Humans, Mice, Animals, F-Box-WD Repeat-Containing Protein 7, Carcinogenesis, Endometrial Neoplasms, Mutation, Mutation, Missense, Driver genes, Endometrial cancer, Fbxw7, Functional models, GEMM, Cancer, Urogenital System

Abstract

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.

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