Genetic and epigenetic modification of mismatch repair genes hMSH2 and hMLH1 in sporadic breast cancer with microsatellite instability

Abstract

Breast cancer is the most common cancer in women, but its pathogenesis is still unclear. Microsatellite instability (MSI) has been identi®ed in breast cancer cells, suggesting an association with mismatch repair defects. To test this hypothesis, we investigated MSI, protein expression of hMSH2 and hMLH1, as well as genetic and epigenetic modi®cations of these two genes in 32 sporadic breast tumors. MSI was identi®ed in 15 cases. Immunohistochemistry analysis revealed that all MSI cases but one had lower than normal expression of hMSH2 (nine cases), hMLH1 (12 cases), or both (seven cases). In tumors with MSI, both genetic and epigenetic modi®cations of these mismatch repair genes were also identi®ed. Eight cases harbored mutations or polymorph- isms in hMSH2 and hMLH1, and 10 exhibited hypermethylation in the promoter region of hMLH1. These results suggest that both genetic and epigenetic alterations of hMSH2 and especially of hMLH1 contribute to genomic instability and tumorigenesis in sporadic breast cancer. Oncogene (2002) 21, 5696 ± 5703. doi:10.1038/sj.onc. 1205683 Keywords: hMSH2; hMLH1; microsatellite instability; hypermethylation; breast cancer