title: Follicular thyroid cancers demonstrate dual activation of PKA and mTOR as modeled by thyroid-specific deletion of Prkar1a and Pten in mice.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  The study was conducted at an academic research laboratory. Human samples were obtained from academic hospitals.
  
  
  METHODS
  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.
  
  
  METHODS
  There were no interventions.
  
  
  METHODS
  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.
authors: 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.
authors: Daphne R
authors: DR
authors: Pringle
authors: Vasily V
authors: VV
authors: Vasko
authors: Lianbo
authors: L
authors: Yu
authors: Parmeet K
authors: PK
authors: Manchanda
authors: Audrey A
authors: AA
authors: Lee
authors: Xiaoli
authors: X
authors: Zhang
authors: Jessica M
authors: JM
authors: Kirschner
authors: Albert F
authors: AF
authors: Parlow
authors: Motoyasu
authors: M
authors: Saji
authors: David
authors: D
authors: Jarjoura
authors: Matthew D
authors: MD
authors: Ringel
authors: Krista M D
authors: KM
authors: La Perle
authors: Lawrence S
authors: LS
authors: Kirschner
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517835:Prkar1a protein, mouse; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse