Abstract 1585: Chronic induction of breast cell carcinogenesis by multiple environmental and dietary carcinogens

Abstract Breast cancer, the most common type of cancer among North American and European women, is mostly sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce breast cell carcinogenesis, we investigated the activity of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the environmental carcinogen benzo[a]pyrene (B[a]P), and the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Non-cancerous human breast epithelial MCF10A cells were exposed to NNK, B[a]P, and PhIP sequentially or in combination and then analyzed for the acquisition of cancerous properties/endpoints. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species (ROS) elevation, and increased cell proliferation. Constitutive endpoints included reduced dependence on growth factors, anchorage-independent growth, Ras-Erk-Nox pathway activation, and increased ROS and cell proliferation. To detect agents that can intervene with cellular carcinogenesis induced by NNK, B[a]P, and PhIP, we investigated the activity of green tea catechins effective in blocking these cancerous endpoints. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP. Co-exposure was more potent than sequential exposure to induce initiation of cellular carcinogenesis measured by induction of transient endpoints in a single exposure and progression of carcinogenesis measured by cellular acquisition of constitutive endpoints in cumulative exposures. Our study also revealed that combined ECG and EGCG, at non-cytotoxic levels, was more effective than individual agents in intervention of cellular carcinogenesis induced by combined NNK, B[a]P, and PhIP. Thus, co-exposure to NNK, B[a]P, and PhIP should be critically examined in epidemiological studies to reveal the impact of these carcinogens in the development of sporadic breast cancer. Use of combined ECG and EGCG should be seriously considered for chemoprevention of breast cell carcinogenesis associated with long-term exposure to environmental and dietary carcinogens. Citation Format: Lenora A. Pluchino, Hwa-Chain R. Wang. Chronic induction of breast cell carcinogenesis by multiple environmental and dietary carcinogens. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1585. doi:10.1158/1538-7445.AM2014-1585