The main objective of the proposed work is to establish whether autoantibodies (aAb) that recognize oxidized DNA bases can be used as biomarkers of cancer (CA) risk. Oxidized bases can be formed in cellular DNA under prooxidant conditions caused by i.e., ionizing radiations, metabolism of xenobiotics and chronic inflammation. The main hypothesis of this application is that elevated titers of aAb, which recognize the 5-hydroxymethyl-2'-deoxyuridine (HMdU) moiety (an oxidized thymidine), are associated with increased risk for breast CA. This hypothesis is based on the investigators preliminary findings, which show that people elaborate anti-HMdU aAb, levels of which are significantly increased in sera of those at high risk for breast CA and those who may develop breast CA within several years. This hypothesis is strengthened by the facts that: 1) chronic inflammation is a contributor to CA; 2) inflammatory processes induce oxidants and oxidative DNA base modification; 3) human breast tumors were shown to contain oxidized bases in their DNA; 4) redox-cycling of estrogens produces oxidants and oxidative DNA damage; 5) elevated bioavailable estradiol and decreased estradiol bound to the sex hormone-binding globulin correlate with breast CA risk, and 6) chemopreventive agents with antioxidant properties inhibit carcinogenesis. The proposed research will: 1) establish whether elevated anti-HMdU aAb titers are associated with risk of breast CA in pre- and post-menopausal women; 2) determine whether there is a positive correlation between anti-HMdU aAb titers in sera and HMdU levels in white blood cell DNA of breast CA patients and controls; and 3) assess the interrelationships among endogenous estrogens, HMdU levels in white blood cell DNA, anti-HMdU aAb titers in sera, diet, and subsequent breast CA. An existing bank of sera samples collected by the New York University Women's Health Study, in which the incidence of breast CA is being related to endogenous estrogens and diet, and which has followed the same subjects for>8 years, will be utilized in the proposed studies. Using a case-control study (including 436 matched sets) nested within a cohort, the sera will be assayed for anti-HMdU aAb by ELISA (enzyme-linked immunosorbent assay), and the DNA foe HMdU by 3H-postlabeling or fluorochrome-postlabeling. Samples will be decoded and relationships established between anti-HMdU aAb and: 1) Breast CA, 2) family history of breast CA,3) HMdU levels, 4) estrogens, and 5) diet.
