We previously demonstrated that the activating Hras1 oncogene mutations found in rat mammary tumors induced by N-nitroso-N-methylurea (NMU) arise as background mutations within cells of the developing gland. We further showed that NMU enhanced the phenotypic penetrance of these pre-existing mutations by initiating alterations in DNA conformation within the promoter region of Hras1 and presumably other target genes. The observed epigenetic response to NMU was present in strains of rats that are genetically predisposed to mammary cancers (such as F344), whereas strains of rats resistant to mammary carcinogenesis (such as Cop) did not show this epigenetic response. Genetic linkage studies by Gould and co-workers have demonstrated that the differential sensitivities to mammary carcinogenesis among rat strains are due to the presence of one or more putative, cell-autonomous, mammary carcinoma suppressor genes in the resistant strains. Other studies have demonstrated that differential sensitivities among rat strains are not due to differences in the rate of DNA adduct formation or removal after exposure. We are using rat GeneChip (Affymetrix) technology in an effort to understand the biochemical basis for this altered response to carcinogen. By comparing the patterns of gene expression as a function of time after exposure to NMU in the resistant and sensitive strains (F344 × Cop)F1 and N2 backcross progeny, we hope to identify the biochemical pathways affected by loss of the putative Cop tumor suppressor gene. Preliminary findings on differences in response to mammary carcinogen exposures will be presented.