title: Increased incidence of endometrioid tumors caused by aberrations in E-cadherin promoter of mismatch repair-deficient mice.
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.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA. kovtun.irina@mayo.edu
authors.forename: Irina V
authors.initials: IV
authors.lastname: Kovtun
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Harris
authors.forename: Aminah
authors.initials: A
authors.lastname: Jatoi
authors.forename: Dragan
authors.initials: D
authors.lastname: Jevremovic
mesh_terms: D000818:Animals; D020137:Base Pair Mismatch; D001483:Base Sequence; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics*; D017931:DNA Primers; D016889:Endometrial Neoplasms / Q000453:epidemiology* / Q000235:genetics; D005260:Female; D015994:Incidence; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic
chemical_list: D015820:Cadherins; D017931:DNA Primers; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein