Abstract 5446: Green tea catechin intervention of reactive oxygen species-mediated ERK pathway activation, DNA damage, and chronically-induced breast cell carcinogenesis

Abstract

Abstract Long-term exposure to low doses of environmental carcinogens contributes to sporadic human breast cancers. Epidemiologic and experimental studies indicate that green tea catechins (GTCs) may interfere with breast cancer development. We have been developing a chronically-induced breast cell carcinogenesis model wherein we repeatedly expose non-cancerous, human breast epithelial MCF10A cells to physiologically-achievable pico-molar concentrations of environmental carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), to progressively induce cellular acquisition of cancer-associated properties, as measurable endpoints. The model is then used as a target to identify non-cytotoxic preventive agents effective in suppressing cellular carcinogenesis. Here, we report a two-step strategy that initially used short-term endpoints that were transiently-induced by a single exposure to NNK and B[a]P. These short-term endpoints were used as targets to detect the ability of individual GTC components to block carcinogenesis. We subsequently used long-term endpoints that were constantly-induced by cumulative exposures to carcinogens as targets to verify and compare the activity of individual GTC components in suppressing carcinogenesis. We detected that a single exposure to NNK and B[a]P resulted in elevation of reactive oxygen species (ROS), leading to ERK pathway activation and induction of cell proliferation and chromosomal DNA damage. GTC components, at non-cytotoxic levels, were able to suppress chronically-induced cellular carcinogenesis by blocking carcinogen-induced ROS elevation, ERK activation, cell proliferation, and DNA damage in each exposure cycle. Our model may help accelerate the identification of agents to prevent carcinogenesis induced by long-term exposure to environmental carcinogens, thereby safely and effectively reducing the health risk of sporadic breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5446. doi:1538-7445.AM2012-5446