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Title: | Functional analysis reveals driver cooperativity and novel mechanisms in endometrial carcinogenesis |
Authors: | Brown, M Leon, A Kedzierska, K Moore, C Belnoue-Davis, HL Flach, S Lydon, JP DeMayo, FJ Lewis, A Bosse, T Tomlinson, I Church, DN |
Keywords: | driver genes;endometrial cancer;Fbxw7;functional models;GEMM |
Issue Date: | 17-Aug-2023 |
Publisher: | EMBO Press |
Citation: | Brown, M. et al. (2023) 'Functional analysis reveals driver cooperativity and novel mechanisms in endometrial carcinogenesis', EMBO Molecular Medicine, 15 (10), e17094, pp. 1 - 18. doi: 10.15252/emmm.202217094. |
Abstract: | Copyright © 2023 The Authors. 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. |
Description: | Data availability Microarray data from this study have been deposited in GEO under accession number GSE232356: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE232356. For more information: Author website: https://www.well.ox.ac.uk/research/research-groups/church-group . Endometrial cancer driver mutations: https://www.intogen.org/search?cancer=UCEC . Endometrial cancer information and patient support: https://peachestrust.org . Supporting Information is available online at: https://www.embopress.org/doi/full/10.15252/emmm.202217094#support-information-section . |
URI: | https://bura.brunel.ac.uk/handle/2438/27770 |
DOI: | https://doi.org/10.15252/emmm.202217094 |
ISSN: | 1757-4676 |
Other Identifiers: | ORCID iD: Matthew Brown https://orcid.org/0000-0002-0299-514X ORCID iD: Charlotte Moore https://orcid.org/0000-0002-7932-1442 ORCID iD: Hayley L Belnoue-Davis https://orcid.org/0000-0003-2914-4932 ORCID iD: Annabelle Lewis https://orcid.org/0000-0003-1876-1927 ORCID iD: David N Church https://orcid.org/0000-0002-4617-962X |
Appears in Collections: | Dept of Life Sciences Research Papers |
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