NITROAROMATICS AND BREAST CANCER

DESCRIPTION (provided by applicant): The cause of most breast cancers remains unknown. Widespread environmental agents (e.g., nitropolycyclic aromatic hydrocarbons [NO2-PAH]) that are known to induce mammary cancer in rodents must be regarded as potential human carcinogens;a representative example is 6-nitrochrysene (6-NC). Studies proposed in this competitive renewal focus on understanding the mechanisms that can account for the remarkable mammary carcinogenicity of 6-NC in rats. We previously showed that trans 1,2-dihydroxy-1,2-dihydro-6- nitrochrysene (1,2-DHD-6-NC) is the proximate carcinogen and characterized the structures of DNA adducts in the rat mammary gland;these adducts were derived not only from simple nitroreduction but also from a combination of ring oxidation and nitroreduction of 6-NC. The structures of these adducts are consistent with the type of mutation spectra observed in the lacl reporter gene in the same target organ in vivo;some of the mutation spectra are identical to those observed in p53 gene in human breast cancer. In the present application, we hypothesize that structural characteristics of certain DNA adducts derived from 6-NC can account for its carcinogenic potency. To test our hypothesis, we will carry out the synthesis of ample materials of 6-NC, and its putative ultimate carcinogenic forms [R,R]- and [S,S]-1,2-DHD-6-NHOH-C, DNA adducts and oligonucelotides containing lesions at hot spots in the p53 and ras gene. Mammary carcinogenesis, mutation frequency, mutation spectra, DNA adducts formation and DNA repair will be assessed. Nothing is known about the repair by mammalian nucleotides excision repair (NER) enzymes of DNA adducts derived from the metabolites of 6-NC either in vitro or in vivo. Furthermore, there is no information about the time dependence after exposure of cells or mammalian tissues and the relative abundance of 6-NC-adducts in different base sequence contexts and how efficiently they are removed by NER process. If not removed by DNA repair mechanisms, it is not established how fast, after exposure, the mutations develop. These issues will be addressed in this project. The proposed studies are requisite to our understanding of the potential risks to the development of breast cancer associated with exposure to 6-NC, a typical NO2-PAH.