The major achievement during the current period has been the extension of our study of the biological significance of stable and depurinating DNA adducts from polycyclic aromatic hydrocarbons (PAH) to catechol estrogens (CE) and their quinones (CE-Q). The combined results from the projects have provided initial information on the estrogen metabolites that form depurinating DNA adducts and can be endogenous initiators of many human cancers. The first goal during the continuation period is to demonstrate, by analyzing estrogen metabolites, conjugates and adducts, that CE-3,4-Q are initiators are breast and prostate cancer, and determine the possible biomarkers for risk of developing these cancers (Project 1). To complement Project 1, the second goal is to demonstrate the role of the critical enzymes, cytochrome P450 (CYP) 19 (aromatase) CYP1A1, CYP 1B1, catechol-O-methyltransferase, and quinone oxidoreductase in the formation, activation and deactivation (protection), respectively, of estrogens in relation to initiation of breast and prostate cancer (Project 2). Third, we will determine the mechanism(s) by which mutations from apurinic sites initiate the process leading to tumors (Project 3). Our fourth goal is to develop new, sensitive and selective laser-based low temperature luminescence techniques for detection of CE- and PAH- derived DNA adducts (Project 4). The final goal is to apply mass spectrometry to highly sensitive and selective analysis of PAH- and CE- modified nucleobases, estrogen conjugates and estrogen metabolites in mixtures., and to assess DNA damage (Project 5). In all of these studies we will develop and apply frontline technology to investigate whether CE-3,4-Q are endogenous tumor initiators that could be at the origin of breast and prostate cancer, and to identify the possible biomarkers for determining cancer risk in humans. The knowledge acquired from these studies will be essential for developing preventive strategies.
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