[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-382936-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-382936-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","alteration-of-tumor-suppressors-changes-the-endometrial-tumor-spectrum","Alteration of tumor suppressors changes the endometrial tumor spectrum","","Alterations of tumor suppressor genes reshape endometrial cancer progression and therapeutic resistance. Using genetically engineered mouse models that combine Fbxw7K482Q, Trp53 loss or gain-of-function mutant p53R172H, and pten deletion, the study maps how each genotype influences tumor onset, grade, and anatomical distribution. Gene expression and TCGA analyses reveal Wnt pathway elevation, with LEF1 and TCF7L2 binding FBXW7, linking suppressor changes to EMT-associated signaling and metastatic programs.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/alteration-of-tumor-suppressors-changes-the-endometrial-tumor-spectrum/382936/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/alteration-of-tumor-suppressors-changes-the-endometrial-tumor-spectrum/382936.png","ImageObject",300,407,{"name":42,"@type":43},"Dipper","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-30","2026-09-24",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",9,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Which tumor suppressor alterations were modeled to study endometrial tumor spectrum changes?","Question",{"text":63,"@type":64},"The study examined Fbxw7K482Q, Trp53 deletion or mutant p53R172H, and pten deletion, including combined genotypes to assess their collective impact on tumor development.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What role does the Wnt pathway play in the altered endometrial tumor spectrum?",{"text":68,"@type":64},"Differential expression and TCGA analysis indicate elevated Wnt signaling in Fbxw7K482Q/pten loss tumors, and the pathway components LEF1 and TCF7L2 were shown to bind the FBXW7 WD40 domain.",{"name":70,"@type":61,"acceptedAnswer":71},"How do the findings distinguish effects of p53 loss versus a specific p53 missense gain-of-function mutant?",{"text":72,"@type":64},"The work emphasizes that the missense mutant has different consequences from p53 loss, with tumor penetrance and acceleration differing across genotypes, and also notes species-specific differences in p53-targeted gene function.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},382936,1790846233,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & 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common gynecological cancer in Europe and the United States is endometrial. Like most cancers, early-stage endometrial cancer has a more favorable prognosis, while high-grade, including endometrioid and nonendometrioid, has the worst prognosis. In endometrioid human tumors, the tumor suppressor genes PTEN and p53 (Trp53) are frequently altered or lost, as identified in datasets from The Cancer Genome Atlas. These suppressors’somatic mutations or loss of gene expression can lead to neoplastic development, tumor progression, and therapeutic resistance. In addition, somatic missense mutations are prevalent in another tumor suppressor, the F-box and WD repeats containing 7 (FBXW7). FBXW7 is part of the SCF-bTrCP ubiquitin complex that signals protein destruction. Specifically, FBXW7 is responsible for binding and facilitating the destabilization of proteins involved in proliferation and migration. Losing the function of multiple tumor suppressors could activate pathways involved in neoplastic progression, malignancy, therapeutic resistance, and formation of different tumor subtypes. The study by Brown et al in this issue of EMBO Mol Med (Brown et al, 2023) provides insight into the complexity of tumor suppressor mutations in malignant endometrial cancer.  \nEMBO Molecular Medicine (2023) 15: e18166 See also: M Brown et al (October 2023)  \nT he authors studied endometrial tumor  \ndevelopment in genetically engi  \nneered mouse models. They examined the pathological characteristics generated  \nby uterus-driven Cre recombination of Fbxw7K482Q (human Fbxw7K479Q), Trp53 deletion, Fbxw7K482Q Trp53 deletion, gain of function Trp53R172H (human mutant p53R175H), Fbxw7K482Q Trp53R172H, deletion pten􀀁/􀀁, and Fbxw7K482Q pten􀀁/ 􀀁 . Mice carrying Fbxw7K482Q alone did not develop endometrial cancer, while those with pten deletion did. Interestingly, mice with Trp53􀀁/ 􀀁 mutation did not develop endometrial tumors, but soft tissue sarcomas at 24 weeks. Similarly, mice carrying p53 hotspot mutant Trp53R172H showed early onset tumor development outside the uterus; however, a small percentage exhibited endometrial carcinomas. Complex genetic recombination showed that mice with pten􀀁/ 􀀁 Fbxw7K482Q developed high-grade endometrial tumors as early as 6 weeks. Interestingly, the presence of both p53R172Hand Fbxw7K482Q also accelerated endometrial tumor formation.  \nDifferential gene expression revealed an elevated Wnt signaling pathway in the Fbxw7K482Q pten􀀁/ 􀀁 tumors compared with the pten􀀁/ 􀀁 tumors. This observation was confirmed by an analysis from the TCGA. A virtual (in silico) screen identified several proteins from the Wnt pathway, including LEF (Lymphoid enhancer element) and TCF7L2 (Transcription factor 7 like-2), as potentially able to bind FBXW7 . Molecular approaches verified that LEF1 and TCF7L2 bound to the WD40 domain of FBXW7 . LEF was detected by immunohistochemistry in Fbxw7K482Q mouse endometrial tumors, and its presence was further increased in pten􀀁/ 􀀁 or Trp53R172H co-mutant animals. Thus, the findings by Brown et al suggest an upregulation of the Wnt pathway during endometrial tumor progression.  \nInterestingly, these mouse models shared some features with human endometrial cancer. Indeed, the invasive nature of cells undergoing EMT requires a network of transcription factors and cellular signaling. The Wnt pathway is known to induce the EMT transcription factor, Snai2 (Saegusa et al, 2009; Kobayashi & Ozawa, 2013), and it would thus be expected that mutations in FBXW7 alone would be sufficient to drive tumor formation; however, this study revealed that endometrial cancers were highly penetrant only when PTEN was deleted (Daikoku et al, 2008) . Loss of PTEN can cause the dysregulation of numerous pathways, including AKT and FAK-Rac (Tamura et al, 1998; Maehama & Dixon, 1999), both involved in tumor migration via Snai-","cbCaijun0u70wRdo","https://ap.wps.com/l/cbCaijun0u70wRdo","pdf",187008,"English","# Introduction\n# Mouse model design and tumor phenotypes\n# Wnt pathway activation and FBXW7 binding\n# EMT links and genotype-specific tumor spectrum\n# Perspective and species considerations","[{\"question\":\"Which tumor suppressor alterations were modeled to study endometrial tumor spectrum changes?\",\"answer\":\"The study examined Fbxw7K482Q, Trp53 deletion or mutant p53R172H, and pten deletion, including combined genotypes to assess their collective impact on tumor development.\"},{\"question\":\"What role does the Wnt pathway play in the altered endometrial tumor spectrum?\",\"answer\":\"Differential expression and TCGA analysis indicate elevated Wnt signaling in Fbxw7K482Q/pten loss tumors, and the pathway components LEF1 and TCF7L2 were shown to bind the FBXW7 WD40 domain.\"},{\"question\":\"How do the findings distinguish effects of p53 loss versus a specific p53 missense gain-of-function mutant?\",\"answer\":\"The work emphasizes that the missense mutant has different consequences from p53 loss, with tumor penetrance and acceleration differing across genotypes, and also notes species-specific differences in p53-targeted gene function.\"}]","Alteration of tumor suppressors changes the endometrial tumor spectrum | PDF",1790253109]