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

Irina V. Kovtun, Kimberly J. Harris, Aminah Jatoi, Dragan Jevremovic

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1085-1092
Number of pages8
JournalCarcinogenesis
Volume32
Issue number7
DOIs
StatePublished - Jul 1 2011

ASJC Scopus subject areas

  • Cancer Research

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