Increasing oxidative damage and loss of mismatch repair enzymes during breast carcinogenesis

This study examined the expression of oxidative damage markers 8-hydroxydeoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal (HNE) and nitrotyrosine using immunohistochemical techniques. In addition, DNA topoisomerase II binding protein 1 (TopBP1) and mismatch repair proteins 2 and 6 (MSH2 and MSH6) were immunostained in a series of 80 stage I invasive breast tumours, 26 in situ breast carcinomas and 12 benign breast hyperplasias. 8-OHdG, HNE and nitrotyrosine expression were considerably weaker in hyperplasias than in in situ lesions, which, in turn, showed less oxidative damage than T1N0 tumours. Hyperplasias and in situ tumours were all, at least moderately, positive for MSH2, and nearly all were positive for MSH6. Nitrotyrosine expression was associated with HNE (P < 0.0005) and 8-OHdG (P = 0.041) in the T1N0 cohort. To conclude, there is increasing oxidative stress during the early steps of breast carcinogenesis. On the other hand, a significant reduction in expression of mismatch repair proteins occurs during the progression of in situ lesions to invasive tumours.