title: Loss of Rb1 in the gastrointestinal tract of Apc1638N mice promotes tumors of the cecum and proximal colon.
abstract: To examine the role of Rb1 in gastrointestinal (GI) tumors, we generated mice with an Apc(1638N) allele, Rb(tm2brn) floxed alleles, and a villin-cre transgene (RBVCA). These animals had exon 19 deleted from Rb1 throughout the GI tract. We have shown previously that Rb1 deficiency is insufficient for GI tumor initiation, with inactivation of an Apc allele capable of overcoming the insufficiency. In this study we demonstrate that RBVCA mice have reduced median survival because of an increase in tumor incidence and multiplicity in the cecum and the proximal colon. Large intestinal tumors are predominantly adenomas, whereas the tumors of the small intestine are a mixture of adenomas and adenocarcinomas. We find truncation mutations to the second Apc allele in tumors of both the large and small intestine. Expression profiles of duodenal and cecal tumors relative to each other show unique gene subsets up and down regulated. Substantial expression patterns compare to human colorectal cancer, including recapitulation of embryonic genes. Our results indicate that Rb1 has significant influence over tumor location in the GI tract, and that both cecal and duodenal tumors initiate through inactivation of Apc. Expression profile analysis indicates the two tumor types differentially regulate distinct sets of genes that are over-expressed in a majority of human colorectal carcinomas.
authors.affiliation: Harvard Partners Center for Genetics and Genomics, Harvard Medical School, Boston, MA 02115, USA. mkucherlapati@rics.bwh.harvard.edu
authors.forename: Melanie H
authors.initials: MH
authors.lastname: Kucherlapati
authors.forename: Kan
authors.initials: K
authors.lastname: Yang
authors.forename: Kunhua
authors.initials: K
authors.lastname: Fan
authors.forename: Mari
authors.initials: M
authors.lastname: Kuraguchi
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Sonkin
authors.forename: Andrew
authors.initials: A
authors.lastname: Rosulek
authors.forename: Martin
authors.initials: M
authors.lastname: Lipkin
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
mesh_terms: D000483:Alleles; D000818:Animals; D002430:Cecal Neoplasms / Q000235:genetics* / Q000378:metabolism; D002432:Cecum / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D041981:Gastrointestinal Tract / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D017491:Genes, APC; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016160:Retinoblastoma Protein / Q000235:genetics / Q000502:physiology*
chemical_list: D016160:Retinoblastoma Protein