title: Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo.
abstract: Inactivation of phosphatase and tensin homology deleted on chromosome 10 (PTEN) is linked to increased PI3K-AKT signaling, enhanced organismal growth, and cancer development. Here we generated and analyzed Pten knock-in mice harboring a C2 domain missense mutation at phenylalanine 341 (Pten(FV)), found in human cancer. Despite having reduced levels of PTEN protein, homozygous Pten(FV/FV) embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous Pten(FV/+) mice develop carcinoma in the thymus, stomach, adrenal medulla, and mammary gland but not in other organs typically sensitive to Pten deficiency, including the thyroid, prostate, and uterus. Progression to carcinoma in sensitive organs ensues in the absence of overt AKT activation. Carcinoma in the uterus, a cancer-resistant organ, requires a second clonal event associated with the spontaneous activation of AKT and downstream signaling. In summary, this PTEN noncatalytic missense mutation exposes a core tumor suppressor function distinct from inhibition of canonical AKT signaling that predisposes to organ-selective cancer development in vivo.
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Enrico
authors: E
authors: Caserta
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Onur
authors: O
authors: Egriboz
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Hui
authors: H
authors: Wang
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Chelsea
authors: C
authors: Martin
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Christopher
authors: C
authors: Koivisto
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Thierry
authors: T
authors: Pecót
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Raleigh D
authors: RD
authors: Kladney
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Changxian
authors: C
authors: Shen
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Kang-Sup
authors: KS
authors: Shim
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Thac
authors: T
authors: Pham
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Matthew K
authors: MK
authors: Karikomi
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Melissa J
authors: MJ
authors: Mauntel
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Sarmila
authors: S
authors: Majumder
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Maria C
authors: MC
authors: Cuitino
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Xing
authors: X
authors: Tang
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Arunima
authors: A
authors: Srivastava
authors: Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210, USA; Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Lianbo
authors: L
authors: Yu
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Julie
authors: J
authors: Wallace
authors: Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210, USA; Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Xiaokui
authors: X
authors: Mo
authors: Department of Biochemistry, McGill University, Montreal, Quebec H3A 1A1, Canada; Rosalind and Morris Goodman Cancer Center, McGill University, Montreal, Quebec H3A 1A1, Canada; Department of Oncology, McGill University, Montreal, Quebec H3A 1A1, Canada;
authors: Morag
authors: M
authors: Park
authors: Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210, USA; Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Soledad A
authors: SA
authors: Fernandez
authors: Department of Internal Medicine, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Robert
authors: R
authors: Pilarski
authors: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Krista M D
authors: KM
authors: La Perle
authors: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Thomas J
authors: TJ
authors: Rosol
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Vincenzo
authors: V
authors: Coppola
authors: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors: Diego H
authors: DH
authors: Castrillon
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Cynthia
authors: C
authors: Timmers
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio 43210, USA;
authors: David E
authors: DE
authors: Cohn
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio 43210, USA;
authors: David M
authors: DM
authors: O'Malley
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Floor
authors: F
authors: Backes
authors: Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Adrian A
authors: AA
authors: Suarez
authors: Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Paul
authors: P
authors: Goodfellow
authors: Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Helen M
authors: HM
authors: Chamberlin
authors: Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors: Erin R
authors: ER
authors: Macrae
authors: Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors: Charles L
authors: CL
authors: Shapiro
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Michael C
authors: MC
authors: Ostrowski
authors: Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
authors: Gustavo
authors: G
authors: Leone
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D005260:Female; D055879:Gene Knock-In Techniques; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics*; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism*; D055550:Protein Stability; D015398:Signal Transduction
chemical_list: D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase
keywords: F341V; breast; cancer; endometrium; pten; uterus