a targeted constitutive mutation in the apc tumor suppressor gene underlies mammary but not intestinal tumorigenesis有针对性的本构apc肿瘤抑制基因的突变是乳腺但不是肠道肿瘤发生.pdfVIP

A Targeted Constitutive Mutation in the Apc Tumor Suppressor Gene Underlies Mammary But Not Intestinal Tumorigenesis 1 1 1 2 3 1 Claudia Gaspar , Patrick Franken , Lia Molenaar , Cor Breukel , Martin van der Valk , Ron Smits , Riccardo Fodde1* 1 Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands, 2 Human and Clinical Genetics Center, LUMC, Leiden, The Netherlands, 3 Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands Abstract Germline mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominant hereditary predisposition to the development of multiple colorectal adenomas and of a broad spectrum of extra-intestinal tumors. Moreover, somatic APC mutations play a rate-limiting and initiating role in the majority of sporadic colorectal cancers. Notwithstanding its multifunctional nature, the main tumor suppressing activity of the APC gene resides in its ability to regulate Wnt/b-catenin signaling. Notably, genotype–phenotype correlations have been established at the APC gene between the length and stability of the truncated proteins encoded by different mutant alleles, the corresponding levels of Wnt/b-catenin signaling activity they encode for, and the incidence and distribution of intestinal and extra-intestinal tumors. Here, we report a novel mouse model, Apc 1572T, obtained by targeting a truncated mutation at codon 1572 in the endogenous Apc gene. This hypomorphic mutant allele results in intermediate levels of Wnt/b-catenin signaling activation when compared with other Apc mutations associated with multifocal intes