title: Intestinal epithelial-specific PTEN inactivation results in tumor formation.
abstract: Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of phosphatidylinositol 3-kinase (PI3K) signaling that is frequently inactivated in colorectal cancer through mutation, loss of heterozygosity, or epigenetic mechanisms. The aim of this study was to determine the effect of intestinal-specific PTEN inactivation on intestinal epithelial homeostasis and tumorigenesis. PTEN was deleted specifically in the intestinal epithelium, by crossing PTEN(Lox/Lox) mice with villin(Cre) mice. PTEN was robustly expressed in the intestinal epithelium and maximally in the differentiated cell compartment. Targeted inactivation of PTEN in the intestinal epithelium of PTEN(Lox/Lox)/villin(Cre) mice was confirmed by genotyping, immunohistochemistry, and qPCR. While intestinal-specific PTEN deletion did not have a major effect on cell fate determination or proliferation in the small intestine, it did increase phosphorylated (p) protein kinase B (AKT) expression in the intestinal epithelium, and 19% of animals developed small intestinal adenomas and adenocarcinomas at 12 mo of age. These tumors demonstrated pAKT and nuclear β-catenin staining, indicating simultaneous activation of the PI3K/AKT and Wnt signaling pathways. These findings demonstrate that, while PTEN inactivation alone has a minimal effect on intestinal homeostasis, it can facilitate tumor promotion upon deregulation of β-catenin/TCF signaling, further establishing PTEN as a bona fide tumor suppressor gene in intestinal cancer.
authors.affiliation: Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, New York, USA.
authors.forename: Do-Sun
authors.initials: DS
authors.lastname: Byun
authors.forename: Naseem
authors.initials: N
authors.lastname: Ahmed
authors.forename: Shannon
authors.initials: S
authors.lastname: Nasser
authors.forename: Joongho
authors.initials: J
authors.lastname: Shin
authors.forename: Sheren
authors.initials: S
authors.lastname: Al-Obaidi
authors.forename: Sanjay
authors.initials: S
authors.lastname: Goel
authors.forename: Georgia A
authors.initials: GA
authors.lastname: Corner
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wilson
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Flanagan
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Augenlicht
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Vincan
authors.forename: John M
authors.initials: JM
authors.lastname: Mariadason
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D051153:Wnt Proteins; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase