title: Characterization of differential gene expression in adrenocortical tumors harboring beta-catenin (CTNNB1) mutations.
abstract: BACKGROUND
  Mutations of β-catenin gene (CTNNB1) are frequent in adrenocortical adenomas (AA) and adrenocortical carcinomas (ACC). However, the target genes of β-catenin have not yet been identified in adrenocortical tumors.
  
  
  OBJECTIVE
  Our objective was to identify genes deregulated in adrenocortical tumors harboring CTNNB1 genetic alterations and nuclear accumulation of β-catenin.
  
  
  METHODS
  Microarray analysis identified a dataset of genes that were differently expressed between AA with CTNNB1 mutations and wild-type (WT) tumors. Within this dataset, the expression profiles of five genes were validated by real time-PCR (RT-PCR) in a cohort of 34 adrenocortical tissues (six AA and one ACC with CTNNB1 mutations, 13 AA and four ACC with WT CTNNB1, and 10 normal adrenal glands) and two human ACC cell lines. We then studied the effects of suppressing β-catenin transcriptional activity with the T-cell factor/β-catenin inhibitors PKF115-584 and PNU74654 on gene expression in H295R and SW13 cells.
  
  
  RESULTS
  RT-PCR analysis confirmed the overexpression of ISM1, RALBP1, and PDE2A and the down-regulation of PHYHIP in five of six AA harboring CTNNB1 mutations compared with WT AA (n = 13) and normal adrenal glands (n = 10). RALBP1 and PDE2A overexpression was also confirmed at the protein level by Western blotting analysis in mutated tumors. ENC1 was specifically overexpressed in three of three AA harboring CTNNB1 point mutations. mRNA expression and protein levels of RALBP1, PDE2A, and ENC1 were decreased in a dose-dependent manner in H295R cells after treatment with PKF115-584 or PNU74654.
  
  
  CONCLUSIONS
  This study identified candidate genes deregulated in CTNNB1-mutated adrenocortical tumors that may lead to a better understanding of the role of the Wnt-β-catenin pathway in adrenocortical tumorigenesis.
authors.affiliation: Division of Endocrinology, Department of Medicine, Centre Hospitalier de l'Université de Montréal-Hôtel-Dieu, 3850 Saint Urbain Street, Montréal, Québec, Canada.
authors.forename: Julien
authors.initials: J
authors.lastname: Durand
authors.forename: Antoine
authors.initials: A
authors.lastname: Lampron
authors.forename: Tania L
authors.initials: TL
authors.lastname: Mazzuco
authors.forename: Audrey
authors.initials: A
authors.lastname: Chapman
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bourdeau
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018246:Adrenocortical Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D009154:Mutation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D051153:Wnt Proteins; D051176:beta Catenin