title: Tissue-Specific Effects of Reduced β-catenin Expression on Adenomatous Polyposis Coli Mutation-Instigated Tumorigenesis in Mouse Colon and Ovarian Epithelium.
abstract: Adenomatous polyposis coli (APC) inactivating mutations are present in most human colorectal cancers and some other cancers. The APC protein regulates the β-catenin protein pool that functions as a co-activator of T cell factor (TCF)-regulated transcription in Wnt pathway signaling. We studied effects of reduced dosage of the Ctnnb1 gene encoding β-catenin in Apc-mutation-induced colon and ovarian mouse tumorigenesis and cell culture models. Concurrent somatic inactivation of one Ctnnb1 allele, dramatically inhibited Apc mutation-induced colon polyposis and greatly extended Apc-mutant mouse survival. Ctnnb1 hemizygous dose markedly inhibited increases in β-catenin levels in the cytoplasm and nucleus following Apc inactivation in colon epithelium, with attenuated expression of key β-catenin/TCF-regulated target genes, including those encoding the EphB2/B3 receptors, the stem cell marker Lgr5, and Myc, leading to maintenance of crypt compartmentalization and restriction of stem and proliferating cells to the crypt base. A critical threshold for β-catenin levels in TCF-regulated transcription was uncovered for Apc mutation-induced effects in colon epithelium, along with evidence of a feed-forward role for β-catenin in Ctnnb1 gene expression and CTNNB1 transcription. The active β-catenin protein pool was highly sensitive to CTNNB1 transcript levels in colon cancer cells. In mouse ovarian endometrioid adenocarcinomas (OEAs) arising from Apc- and Pten-inactivation, while Ctnnb1 hemizygous dose affected β-catenin levels and some β-catenin/TCF target genes, Myc induction was retained and OEAs arose in a fashion akin to that seen with intact Ctnnb1 gene dose. Our findings indicate Ctnnb1 gene dose exerts tissue-specific differences in Apc mutation-instigated tumorigenesis. Differential expression of selected β-catenin/TCF-regulated genes, such as Myc, likely underlies context-dependent effects of Ctnnb1 gene dosage in tumorigenesis.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Jie-Yu
authors.initials: JY
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Wiese
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Maranne E
authors.initials: ME
authors.lastname: Green
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Megan
authors.initials: M
authors.lastname: Green
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Aytekin
authors.initials: A
authors.lastname: Akyol
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Badal C
authors.initials: BC
authors.lastname: Roy
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Fearon
mesh_terms: D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics*; D005260:Female; D017491:Genes, APC; D051379:Mice; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051176:beta Catenin