Hypomethylation of mismatch repair genes MLH1 and MSH2 is associated with chemotolerance of breast carcinoma: Clinical significance

Abstract

Background and objectives: The aim of the study was to understand the importance of mismatch repair genes MLH1 and MSH2 in chemotolerance and prognosis of breast carcinoma (BC).

Methods: First, the alterations (deletion/methylation/expression) of MLH1 and MSH2 were analyzed in 45 neoadjuvant chemotherapy (NACT)-treated and 133 pretherapeutic BC samples. The chemotolerant BC cells were characterized by treating two BC cell lines MCF-7 and MDA MB 231 with two anthracycline antitumor antibiotics, doxorubicin and nogalamycin.

Results: The deletion frequencies were 32% to 38% in MLH1/MSH2 genes and promoter methylation frequencies were 49% to 62% in MLH1 and 41% to 51% in MSH2 in both NACT-treated and pretherapeutic samples. The overall alteration of MLH1 and MSH2 was 58% to 71% in the samples. Reduced messenger RNA (mRNA) and protein expression were found in both the genes and it showed concordance with the molecular alterations. NACT-treated patients showed better prognosis. The chemotherapeutic drug induced increased mRNA/protein expression of the genes in BC cell lines was due to their promoter hypomethylation, as analyzed by quantitative methylation assay. This phenomenon was also evident in NACT-treated BC samples.

Conclusion: MLH1/MSH2 genes play a critical role in the development of BC. Hypomethylation of MLH1/MSH2 genes might be important in chemotolerance of the disease.

Keywords: MLH1/MSH2; breast carcinoma; doxorubicin/nogalamycin; neoadjuvant chemotherapy; promoter hypomethylation.