Abnormalities of the APC/beta-catenin pathway in endometrial cancer

Oncogene. 2002 Nov 14;21(52):7981-90. doi: 10.1038/sj.onc.1205924.


The activation of the APC/beta-catenin signalling pathway due to beta-catenin mutations has been implicated in the development of a subset of endometrial carcinomas (ECs). However, up to 25% of ECs have beta-catenin nuclear accumulation without evidence of beta-catenin mutations, suggesting alterations of other molecules that can modulate the Wnt pathway, such as APC, gamma-catenin, AXIN1 and AXIN2. We investigated the expression pattern of beta- and gamma-catenin in a group of 128 endometrial carcinomas, including 95 endometrioid endometrial carcinomas (EECs) and 33 non-endometrioid endometrial carcinomas (NEECs). In addition, we evaluated the presence of loss of heterozygosity and promoter hypermethylation of the APC gene and mutations in the APC, beta- and gamma-catenin, AXIN1, AXIN2, and RAS genes, and phospho-Akt expression. No APC mutations were detected but LOH at the APC locus was found in 24.3% of informative cases. APC promoter 1A hypermethylation was observed in 46.6% of ECs, and was associated with the endometrioid phenotype (P=0.034) and microsatellite instability (P=0.008). Neither LOH nor promoter hypermethylation of APC was associated with nuclear catenin expression. Nuclear beta-catenin expression was found in 31.2% of EECs and 3% of NEECs (P=0.002), and was significantly associated with beta-catenin gene exon 3 mutations (P<0.0001). beta-catenin gene exon 3 mutations were associated with the endometrioid phenotype, and were detected in 14 (14.9%) EECs, but in none of the NEECs (P=0.02). gamma-catenin nuclear expression was found in 10 ECs; it was not associated with the histological type but was associated with more advanced stages (P=0.042). No mutations in gamma-catenin, AXIN1 and 2 genes were detected in this series. Neither RAS mutations nor phospho-Akt expression, which were found in 16 and 27.6% of the cases, respectively, were associated with beta-catenin nuclear expression. Our results demonstrated a high prevalence of alterations in molecules of the APC/beta-catenin pathway, but only mutations in beta-catenin gene are associated with aberrant nuclear localization of beta-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli Protein / metabolism*
  • Adult
  • Aged
  • Aged, 80 and over
  • Axin Protein
  • Base Sequence
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • DNA Methylation
  • DNA Primers
  • Endometrial Neoplasms / genetics
  • Endometrial Neoplasms / metabolism*
  • Female
  • Genes, ras
  • Humans
  • Loss of Heterozygosity
  • Middle Aged
  • Mutation
  • Promoter Regions, Genetic
  • Proteins / genetics
  • Repressor Proteins*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • beta Catenin


  • AXIN1 protein, human
  • AXIN2 protein, human
  • Adenomatous Polyposis Coli Protein
  • Axin Protein
  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • DNA Primers
  • Proteins
  • Repressor Proteins
  • Trans-Activators
  • beta Catenin