PMID- 24512487 OWN - NLM STAT- MEDLINE DCOM- 20140710 LR - 20211203 IS - 1945-7197 (Electronic) IS - 0021-972X (Print) IS - 0021-972X (Linking) VI - 99 IP - 5 DP - 2014 May TI - Follicular thyroid cancers demonstrate dual activation of PKA and mTOR as modeled by thyroid-specific deletion of Prkar1a and Pten in mice. PG - E804-12 LID - 10.1210/jc.2013-3101 [doi] AB - CONTEXT: Thyroid cancer is the most common form of endocrine cancer, and it is a disease whose incidence is rapidly rising. Well-differentiated epithelial thyroid cancer can be divided into papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Although FTC is less common, patients with this condition have more frequent metastasis and a poorer prognosis than those with PTC. OBJECTIVE: The objective of this study was to characterize the molecular mechanisms contributing to the development and metastasis of FTC. DESIGN: We developed and characterized mice carrying thyroid-specific double knockout of the Prkar1a and Pten tumor suppressor genes and compared signaling alterations observed in the mouse FTC to the corresponding human tumors. SETTING: The study was conducted at an academic research laboratory. Human samples were obtained from academic hospitals. PATIENTS: Deidentified, formalin-fixed, paraffin-embedded (FFPE) samples were analyzed from 10 control thyroids, 30 PTC cases, five follicular variant PTC cases, and 10 FTC cases. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Mouse and patient samples were analyzed for expression of activated cAMP response element binding protein, AKT, ERK, and mammalian target of rapamycin (mTOR). Murine FTCs were analyzed for differential gene expression to identify genes associated with metastatic progression. RESULTS: Double Prkar1a-Pten thyroid knockout mice develop FTC and recapitulate the histology and metastatic phenotype of the human disease. Analysis of signaling pathways in FTC showed that both human and mouse tumors exhibited strong activation of protein kinase A and mTOR. The development of metastatic disease was associated with the overexpression of genes required for cell movement. CONCLUSIONS: These data imply that the protein kinase A and mTOR signaling cascades are important for the development of follicular thyroid carcinogenesis and may suggest new targets for therapeutic intervention. Mouse models paralleling the development of the stages of human FTC should provide important new tools for understanding the mechanisms of FTC development and progression and for evaluating new therapeutics. FAU - Pringle, Daphne R AU - Pringle DR AD - Departments of Molecular, Virology, Immunology, and Medical Genetics (D.R.P., P.K.M., A.A.L., J.M.K., L.S.K.) and Veterinary Biosciences (K.M.D.L.P.), Center for Biostatistics (L.Y., X.Z., D.J.), and Division of Endocrinology, Diabetes, and Metabolism (M.S., M.D.R., L.S.K.), The Ohio State University, Columbus, Ohio 43210; Department of Pediatrics (V.V.V.), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814; and National Hormone and Peptide Program (A.F.P.), Harbor-UCLA Medical Center, Torrance, California 90509. FAU - Vasko, Vasily V AU - Vasko VV FAU - Yu, Lianbo AU - Yu L FAU - Manchanda, Parmeet K AU - Manchanda PK FAU - Lee, Audrey A AU - Lee AA FAU - Zhang, Xiaoli AU - Zhang X FAU - Kirschner, Jessica M AU - Kirschner JM FAU - Parlow, Albert F AU - Parlow AF FAU - Saji, Motoyasu AU - Saji M FAU - Jarjoura, David AU - Jarjoura D FAU - Ringel, Matthew D AU - Ringel MD FAU - La Perle, Krista M D AU - La Perle KM FAU - Kirschner, Lawrence S AU - Kirschner LS LA - eng GR - R01 CA112268/CA/NCI NIH HHS/United States GR - CA16058/CA/NCI NIH HHS/United States GR - R01 CA170249/CA/NCI NIH HHS/United States GR - CA112268/CA/NCI NIH HHS/United States GR - P30 CA016058/CA/NCI NIH HHS/United States GR - P01CA124570/CA/NCI NIH HHS/United States GR - P01 CA124570/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140210 PL - United States TA - J Clin Endocrinol Metab JT - The Journal of clinical endocrinology and metabolism JID - 0375362 RN - 0 (Cyclic AMP-Dependent Protein Kinase RIalpha Subunit) RN - 0 (Prkar1a protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (Pten protein, mouse) SB - IM MH - Adenocarcinoma, Follicular/genetics/*metabolism/pathology MH - Animals MH - Cyclic AMP-Dependent Protein Kinase RIalpha Subunit/genetics/*metabolism MH - Cyclic AMP-Dependent Protein Kinases/*metabolism MH - Disease Models, Animal MH - Humans MH - Mice MH - Mice, Knockout MH - PTEN Phosphohydrolase/genetics/*metabolism MH - Signal Transduction/physiology MH - TOR Serine-Threonine Kinases/*metabolism MH - Thyroid Gland/metabolism/pathology MH - Thyroid Neoplasms/genetics/*metabolism/pathology PMC - PMC4010710 EDAT- 2014/02/12 06:00 MHDA- 2014/07/11 06:00 PMCR- 2015/05/01 CRDT- 2014/02/12 06:00 PHST- 2014/02/12 06:00 [entrez] PHST- 2014/02/12 06:00 [pubmed] PHST- 2014/07/11 06:00 [medline] PHST- 2015/05/01 00:00 [pmc-release] AID - 13-3101 [pii] AID - 10.1210/jc.2013-3101 [doi] PST - ppublish SO - J Clin Endocrinol Metab. 2014 May;99(5):E804-12. doi: 10.1210/jc.2013-3101. Epub 2014 Feb 10.