Eosinophils as Mediators of DNA Oxidative Damage in Breast Cancer

摘要

The overall goal of this proposal were to test the hypothesis that eosinophils promote DNA oxidative damage in breast carcinoma. DNA oxidative damage is linked to mutation, transformation and cancer development and eosinophil peroxidase (EPO), a hemoprotein secreted from eosinophils, is present in the majority of breast cancer biopsies. Our initial aim was to determine whether EPO promotes oxidative damage of cellular DNA through formation of mutagenic hydroxyl radical (DN)-generated bases. We have shown (Biochemistry, (2000) 39:5474) that activated leukocytes can oxidatively damage DNA, ANA and the nucleotide pool through halide-dependent formation of OH. 0H-dependent damage of DNA was quantified by monitoring the content of 8-hydroxyguanine (SOND), an established OH-specific DNA oxidation product that is mutagenic and implicated in breast cancer de:development and progression to metastatic disease. To test the hypothesis that EPO promotes DNA oxidative damage in human breast carcinoma, we have identified a family of novel brominated DNA oxidation products. These may serve as 'molecular fingerprints' for DNA damage by the EPO pathway of eosinophils. Results of our studies identifying brominated bases by mess spectrometry ware recently published (Biochemistry, (2001) 40:2041-2051) . Nest recently we have shown that markers of nitric oxide-derived oxidants, species formed by eosinophils, are correlated microvascular density in breast carcinoma (Breast Cancer Research and Treatment (2002) 74:271-278). We are presently performing studies aimed at quantifying these EPD-specific brominated bases in a well-characterized repository of breast carcinoma and microscopically normal breast tissue specimens.