Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo
- Enrico Caserta1,2,3,15,
- Onur Egriboz1,2,3,15,
- Hui Wang1,2,3,15,
- Chelsea Martin1,2,3,15,
- Christopher Koivisto1,2,3,
- Thierry Pecót1,2,3,
- Raleigh D. Kladney1,2,3,
- Changxian Shen1,2,3,
- Kang-Sup Shim1,2,3,
- Thac Pham1,2,3,
- Matthew K. Karikomi1,2,3,
- Melissa J. Mauntel1,2,3,
- Sarmila Majumder1,2,3,
- Maria C. Cuitino1,2,3,
- Xing Tang1,2,3,
- Arunima Srivastava1,2,3,
- Lianbo Yu4,5,
- Julie Wallace1,2,3,
- Xiaokui Mo4,5,
- Morag Park6,7,8,
- Soledad A. Fernandez4,5,
- Robert Pilarski9,
- Krista M.D. La Perle10,
- Thomas J. Rosol10,
- Vincenzo Coppola1,3,
- Diego H. Castrillon11,
- Cynthia Timmers1,
- David E. Cohn12,
- David M. O'Malley12,
- Floor Backes12,
- Adrian A. Suarez13,
- Paul Goodfellow3,12,
- Helen M. Chamberlin2,
- Erin R. Macrae14,
- Charles L. Shapiro14,
- Michael C. Ostrowski1,3 and
- Gustavo Leone1,2,3
- 1Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA;
- 2Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA;
- 3Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
- 4Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210, USA;
- 5Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
- 6Department of Biochemistry, McGill University, Montreal, Quebec H3A 1A1, Canada;
- 7Rosalind and Morris Goodman Cancer Center, McGill University, Montreal, Quebec H3A 1A1, Canada;
- 8Department of Oncology, McGill University, Montreal, Quebec H3A 1A1, Canada;
- 9Department of Internal Medicine, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA;
- 10Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
- 11Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 12Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University, Columbus, Ohio 43210, USA;
- 13Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA;
- 14Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA
- Corresponding authors: gustavo.leone{at}osumc.edu, michael.ostrowski{at}osumc.edu
-
↵15 These authors contributed equally to this work.
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 (PtenFV), found in human cancer. Despite having reduced levels of PTEN protein, homozygous PtenFV/FV embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous PtenFV/+ 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.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.262568.115.
- Received March 23, 2015.
- Accepted July 27, 2015.
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