title: Insulin-like growth factor--phosphatidylinositol 3 kinase signaling in canine cortisol-secreting adrenocortical tumors.
abstract: BACKGROUND
  Hypercortisolism is a common endocrine disorder in dogs, caused by a cortisol-secreting adrenocortical tumor (AT) in approximately 15% of cases. In adrenocortical carcinomas of humans, activation of the phosphatidylinositol 3 kinase (PI3K) signaling pathway by insulin-like growth factor (IGF) signaling represents a promising therapeutic target.
  
  
  OBJECTIVE
  To investigate the involvement of PI3K signaling in the pathogenesis of ATs in dogs and to identify pathway components that may hold promise as future therapeutic targets or as prognostic markers.
  
  
  METHODS
  Analyses were performed on 36 canine cortisol-secreting ATs (11 adenomas and 25 carcinomas) and 15 normal adrenal glands of dogs.
  
  
  METHODS
  mRNA expression analysis was performed for PI3K target genes, PI3K inhibitor phosphatase and tensin homolog (PTEN), IGFs, IGF receptors, IGF binding proteins and epidermal growth factor receptors. Mutation analysis was performed on genes encoding PTEN and PI3K catalytic subunit (PIK3CA).
  
  
  RESULTS
  Target gene expression indicated PI3K activation in carcinomas, but not in adenomas. No amino acid-changing mutations were detected in PTEN or PIK3CA and no significant alterations in IGF-II or IGFR1 expression were detected. In carcinomas, ERBB2 expression tended to be higher than in normal adrenal glands, and higher expression of inhibitor of differentiation 1 and 2 (ID1 and ID2) was detected in carcinomas with recurrence within 2.5 years after adrenalectomy.
  
  
  CONCLUSIONS
  Based on these results, ERBB2 might be a promising therapeutic target in ATs in dogs, whereas ID1 and 2 might be valuable as prognostic markers and therapeutic targets.
authors.affiliation: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: M M J
authors.initials: MM
authors.lastname: Kool
authors.forename: S
authors.initials: S
authors.lastname: Galac
authors.forename: N
authors.initials: N
authors.lastname: van der Helm
authors.forename: S
authors.initials: S
authors.lastname: Corradini
authors.forename: H S
authors.initials: HS
authors.lastname: Kooistra
authors.forename: J A
authors.initials: JA
authors.lastname: Mol
mesh_terms: D000236:Adenoma / Q000378:metabolism / Q000662:veterinary; D000306:Adrenal Cortex Neoplasms / Q000378:metabolism / Q000662:veterinary*; D000818:Animals; D002277:Carcinoma / Q000378:metabolism / Q000662:veterinary; D004283:Dog Diseases / Q000378:metabolism*; D004285:Dogs; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006854:Hydrocortisone / Q000378:metabolism*; D008297:Male; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger; D015398:Signal Transduction / Q000502:physiology*; D013002:Somatomedins / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D013002:Somatomedins; D004815:Epidermal Growth Factor; D058539:Phosphatidylinositol 3-Kinase; D051059:PTEN Phosphohydrolase; D006854:Hydrocortisone
keywords: Adrenal; Dog; Hypercortisolism; Insulin-like growth factor; Phosphatidylinositol 3 kinase