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In light of epidemiological investigations that have suggested that exposure to tobacco and environmental carcinogens increase the risk of developing human breast cancer, we have taken a cellular approach of analyzing the acquisition of cancerous properties induced by repeated exposure to pico-molar concentrations of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and environmental carcinogen benzo[a]pyrene (B[a]P) in immortalized non-cancerous human breast epithelial MCF10A cells. Increasing exposures of MCF10A cells to NNK and B[a]P result in carcinogenesis progressed from a stage of immortalization to precancerous sub-stages of acquiring a reduced dependence on growth factors and acquiring anchorage-independent growth. Using Matrigel for MCF10A cells to form size-restricted acini, we detected that exposures to NNK and B[a]P resulted in altered acinar conformation. Analysis of gene expression profiles by cDNA microarrays revealed up- and down-regulated genes associated with NNK- and B[a]P-induced carcinogenesis. Using this cellular carcinogenesis model as a target system to identify anticancer agents, we detected that grape seed proanthocyanadin extract and green tea catechin extract significantly suppressed NNK- and B[a]P-induced carcinogenesis of MCF10A cells. Our studies provide a carcinogenesis-cellular model mimicking the accumulative exposure to carcinogens in the progression of human breast epithelial cells to increasingly acquire cancerous properties, as likely occurs in the development of precancerous human breast cells. Our cellular model also serves as a cost-efficient, in vitro system to identify preventive agents that inhibit human breast cell carcinogenesis induced by chronic exposures to carcinogens.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA