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DC Field | Value | Language |
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dc.contributor.author | Brown, M | - |
dc.contributor.author | Leon, A | - |
dc.contributor.author | Kedzierska, K | - |
dc.contributor.author | Moore, C | - |
dc.contributor.author | Belnoue-Davis, HL | - |
dc.contributor.author | Flach, S | - |
dc.contributor.author | Lydon, JP | - |
dc.contributor.author | DeMayo, FJ | - |
dc.contributor.author | Lewis, A | - |
dc.contributor.author | Bosse, T | - |
dc.contributor.author | Tomlinson, I | - |
dc.contributor.author | Church, DN | - |
dc.date.accessioned | 2023-11-30T15:38:02Z | - |
dc.date.available | 2023-08-17 | - |
dc.date.available | 2023-11-30T15:38:02Z | - |
dc.date.issued | 2023-08-17 | - |
dc.identifier | ORCID iD: Matthew Brown https://orcid.org/0000-0002-0299-514X | - |
dc.identifier | ORCID iD: Charlotte Moore https://orcid.org/0000-0002-7932-1442 | - |
dc.identifier | ORCID iD: Hayley L Belnoue-Davis https://orcid.org/0000-0003-2914-4932 | - |
dc.identifier | ORCID iD: Annabelle Lewis https://orcid.org/0000-0003-1876-1927 | - |
dc.identifier | ORCID iD: David N Church https://orcid.org/0000-0002-4617-962X | - |
dc.identifier.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. | en_US |
dc.identifier.issn | 1757-4676 | - |
dc.identifier.uri | https://bura.brunel.ac.uk/handle/2438/27770 | - |
dc.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. | en_US |
dc.description | 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 . | - |
dc.description | Supporting Information is available online at: https://www.embopress.org/doi/full/10.15252/emmm.202217094#support-information-section . | - |
dc.description.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. | en_US |
dc.description.sponsorship | Cancer Research UK (CRUK). Grant Number: C26642/A27963; KWF Kankerbestrijding; HHS¦NIH¦Office of Extramural Research, National Institutes of Health (OER). Grant Numbers: RO1 HD042311, Z1AES103311; Medical Research Council; Oxford NIHR Biomedical Research Centre (BRC); Verein zur F#x00F6;rderung von Wissenschaft und Forschung an der Medizinischen Fakult#x00E4;t der LMU M#x00FC;nchen e.. Grant Number: 203141/Z/16/Z; Wellcome Trust (WT). | en_US |
dc.format.medium | Print-Electronic | - |
dc.language | English | - |
dc.language.iso | en_US | en_US |
dc.publisher | EMBO Press | en_US |
dc.rights | Copyright © 2023 The Authors. Published under the terms of the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/). This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. | - |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | - |
dc.subject | driver genes | en_US |
dc.subject | endometrial cancer | en_US |
dc.subject | Fbxw7 | en_US |
dc.subject | functional models | en_US |
dc.subject | GEMM | en_US |
dc.title | Functional analysis reveals driver cooperativity and novel mechanisms in endometrial carcinogenesis | en_US |
dc.type | Article | en_US |
dc.identifier.doi | https://doi.org/10.15252/emmm.202217094 | - |
dc.relation.isPartOf | EMBO Molecular Medicine | - |
pubs.issue | 10 | - |
pubs.publication-status | Published | - |
pubs.volume | 15 | - |
dc.identifier.eissn | 1757-4684 | - |
dc.rights.holder | The Authors | - |
Appears in Collections: | Dept of Life Sciences Research Papers |
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