Open AccessIncreased incidence of endometrioid tumors caused by aberrations in E-cadherin promoter of mismatch repair-deficient mice
Author(s) -
Irina V. Kovtun,
Kimberly J. Harris,
Aminah Jatoi,
Dragan Jevremović
Publication year - 2011
Publication title -
carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.688
H-Index - 204
eISSN - 1460-2180
pISSN - 0143-3334
DOI - 10.1093/carcin/bgr080
Subject(s) - cdh1 , msh2 , cadherin , carcinogenesis , cancer research , biology , uterus , endometrial cancer , mlh1 , cancer , dna mismatch repair , dna repair , gene , endocrinology , genetics , cell
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.