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dc.contributor.authorBronson, R T
dc.contributor.authorParisi, Tiziana
dc.contributor.authorLees, Jacqueline
dc.date.accessioned2016-12-05T21:07:23Z
dc.date.available2016-12-05T21:07:23Z
dc.date.issued2015-03
dc.date.submitted2014-11
dc.identifier.issn0950-9232
dc.identifier.issn1476-5594
dc.identifier.urihttp://hdl.handle.net/1721.1/105724
dc.description.abstractThe retinoblastoma gene (Rb) is mutated at significant frequency in various human epithelial tumors, including colorectal cancer, and is strongly associated with metastatic disease. However, sole inactivation of Rb in the mouse has so far failed to yield epithelial cancers. Here, we specifically inactivate Rb and/or p53 in the urogenital epithelium and the intestine. We find that loss of both tumor suppressors is unable to yield tumors in the transitional epithelium lining the bladder, kidneys and ureters. Instead, these mice develop highly metastatic tumors of neuroendocrine, not epithelial, origin within the urogenital tract to give prostate cancer in the males and vaginal tumors in the females. Additionally, we discovered that the sole inactivation of Rb in the intestine was sufficient to induce formation of metastatic colorectal adenocarcinomas. These tumors closely mirror the human disease in regard to age of onset, histological appearance, invasiveness and metastatic potential. Like most human colorectal carcinomas, our murine Rbdeficient tumors demonstrate genomic instability and they show activation of β-catenin. Deregulation of the Wnt/β-catenin pathway is specific to the intestinal tumors, as genomic instability but not activation of β-catenin was observed in the neuroendocrine tumors. To date, attempts to generate genetically engineered mouse models of colorectal cancer tumors have yielded mostly cancer of the small intestine, which rarely occurs in humans. Our system provides the opportunity to accurately model and study colorectal cancer in the mouse via a single gene mutation.en_US
dc.description.sponsorshipNational Cancer Institute (U.S.) (Grants P30-CA14051, P01-CA42063 and RO1-CA121921)en_US
dc.language.isoen_US
dc.publisherNature Publishing Groupen_US
dc.relation.isversionofhttp://dx.doi.org/10.1038/onc.2015.30en_US
dc.rightsCreative Commons Attribution-Noncommercial-Share Alikeen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/en_US
dc.sourcePMCen_US
dc.titleInactivation of the retinoblastoma gene yields a mouse model of malignant colorectal canceren_US
dc.typeArticleen_US
dc.identifier.citationParisi, T, R T Bronson, and J A Lees. “Inactivation of the Retinoblastoma Gene Yields a Mouse Model of Malignant Colorectal Cancer.” Oncogene 34.48 (2015): 5890–5899.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentKoch Institute for Integrative Cancer Research at MITen_US
dc.contributor.mitauthorParisi, Tiziana
dc.contributor.mitauthorLees, Jacqueline
dc.relation.journalOncogeneen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsParisi, T; Bronson, R T; Lees, J Aen_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0001-9451-2194
mit.licenseOPEN_ACCESS_POLICYen_US


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