title: Fbw7 and p53 cooperatively suppress advanced and chromosomally unstable intestinal cancer.
abstract: Colorectal cancer (CRC) remains a major cause of cancer mortality worldwide. Murine models have yielded critical insights into CRC pathogenesis, but they often fail to recapitulate advanced-disease phenotypes, notably metastasis and chromosomal instability (CIN). New models are thus needed to understand disease progression and to develop therapies. We sought to model advanced CRC by inactivating two tumor suppressors that are mutated in human CRCs, the Fbw7 ubiquitin ligase and p53. Here we report that Fbw7 deletion alters differentiation and proliferation in the gut epithelium and stabilizes oncogenic Fbw7 substrates, such as cyclin E and Myc. However, Fbw7 deletion does not cause tumorigenesis in the gut. In contrast, codeletion of both Fbw7 and p53 causes highly penetrant, aggressive, and metastatic adenocarcinomas, and allografts derived from these tumors form highly malignant adenocarcinomas. In vitro evidence indicates that Fbw7 ablation promotes genetic instability that is suppressed by p53, and we show that most Fbw7⁻/⁻; p53⁻/⁻ carcinomas exhibit a CIN⁺ phenotype. We conclude that Fbw7 and p53 synergistically suppress adenocarcinomas that mimic advanced human CRC with respect to histopathology, metastasis, and CIN. This model thus represents a novel tool for studies of advanced CRC as well as carcinogenesis associated with ubiquitin pathway mutations.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Grim
authors.forename: Sue E
authors.initials: SE
authors.lastname: Knoblaugh
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Guthrie
authors.forename: Amanda
authors.initials: A
authors.lastname: Hagar
authors.forename: Jherek
authors.initials: J
authors.lastname: Swanger
authors.forename: Jessica
authors.initials: J
authors.lastname: Hespelt
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Delrow
authors.forename: Tom
authors.initials: T
authors.lastname: Small
authors.forename: William M
authors.initials: WM
authors.lastname: Grady
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Clurman
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D043171:Chromosomal Instability; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases