Increased incidence of endometrioid tumors caused by aberrations in E-cadherin promoter of mismatch repair-deficient mice

Carcinogenesis. 2011 Jul;32(7):1085-92. doi: 10.1093/carcin/bgr080. Epub 2011 May 5.

Abstract

Loss of E-cadherin expression is a critical step in the development and progression of gynecological tumors. Study of the precise role of E-cadherin has been hampered by the lack of satisfactory mouse model for E-cadherin deficiency. Likewise, DNA mismatch repair (MMR) is implicated in gynecological tumorigenesis, but knockout of MMR in mice predominantly causes hematologic neoplasms. Here, we show that combined disruption of E-cadherin and DNA MMR pathways increases incidence of endometrioid tumors in mice. Twenty percent of mice knockout for Msh2 enzyme and hemizygous for E-cadherin [Msh2(-/-)/Cdh1(+/-)] developed endometrioid-like tumors in the ovary, uterus and genital area. Characteristic of these tumors was a complete loss of E-cadherin expression. Sequence analysis of E-cadherin promoter region demonstrated that the loss of E-cadherin expression is caused by inactivating mutations, implying that E-cadherin is a mutational target in Msh2-deficient mice. In addition, Msh2(-/-)/Cdh1(+/-) mice showed a reduction in overall survival as compared with their Msh2(-/-) counterparts due to the development of more aggressive lymphomas, suggesting a specific role of E-cadherin in lymphomagenesis. In conclusion, Msh2(-/-)/Cdh1(+/-) mice provide a good model of gynecological tumorigenesis and may be useful for testing molecular target-specific therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Pair Mismatch*
  • Base Sequence
  • Blotting, Western
  • Cadherins / genetics*
  • DNA Primers
  • Endometrial Neoplasms / epidemiology*
  • Endometrial Neoplasms / genetics
  • Female
  • Incidence
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MutS Homolog 2 Protein / genetics
  • MutS Homolog 2 Protein / physiology
  • Promoter Regions, Genetic*

Substances

  • Cadherins
  • DNA Primers
  • Msh2 protein, mouse
  • MutS Homolog 2 Protein