title: Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice.
abstract: The tumor suppressor SMAD4, also known as DPC4, deleted in pancreatic cancer, is a central mediator of TGF-beta signaling. It was previously shown that mice homozygous for a null mutation of Smad4 (Smad4-/-) died prior to gastrulation displaying impaired extraembryonic membrane formation and endoderm differentiation. Here we show that Smad4+/- mice began to develop polyposis in the fundus and antrum when they were over 6 - 12 months old, and in the duodenum and cecum in older animals at a lower frequency. With increasing age, polyps in the antrum show sequential changes from hyperplasia, to dysplasia, in-situ carcinoma, and finally invasion. These alterations are initiated by a dramatic expansion of the gastric epithelium where Smad4 is expressed. However, loss of the remaining Smad4 wild-type allele was detected only in later stages of tumor progression, suggesting that haploinsufficiency of Smad4 is sufficient for tumor initiation. Our data also showed that overexpression of TGF-beta1 and Cyclin D1 was associated with increased proliferation of gastric polyps and tumors. These studies demonstrate that Smad4 functions as a tumor suppressor in the gastrointestinal tract and also provide a valuable model for screening factors that promote or prevent gastric tumorigenesis.
authors.affiliation: Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, MD 20892, USA.
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.forename: S G
authors.initials: SG
authors.lastname: Brodie
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.forename: Y H
authors.initials: YH
authors.lastname: Im
authors.forename: W T
authors.initials: WT
authors.lastname: Parks
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: Y X
authors.initials: YX
authors.lastname: Zhou
authors.forename: M
authors.initials: M
authors.lastname: Weinstein
authors.forename: S J
authors.initials: SJ
authors.lastname: Kim
authors.forename: C X
authors.initials: CX
authors.lastname: Deng
mesh_terms: D000367:Age Factors; D000818:Animals; D019938:Cyclin D1 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006238:Haploidy; D019656:Loss of Heterozygosity; D051379:Mice; D011127:Polyps / Q000235:genetics* / Q000473:pathology; D051901:Smad4 Protein; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D019938:Cyclin D1