Abstract
Breast cancer is the most common type of cancer affecting women in North America and Europe. More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce cellular carcinogenesis, we studied the activity of environmental carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), and dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) using our breast cell carcinogenesis model. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP in both non-cancerous and cancerous breast cells. Co-exposure was more potent than sequential exposure to combined NNK and B[a]P followed by PhIP in inducing carcinogenesis. Initiation of carcinogenesis was measured by transient endpoints induced in a single exposure, while progression of carcinogenesis was measured by acquisition of constitutive endpoints in cumulative exposures. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species elevation, and increased cellular proliferation. Constitutive endpoints included various cancer-associated properties and signaling modulators, as well as enrichment of cancer stem-like cell population and activation of the epithelial-to-mesenchymal transition program. Using transient and constitutive endpoints as targets, we detected that a combination of the green tea catechins 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, use of combined ECG and EGCG should be seriously considered for early intervention of breast cell carcinogenesis associated with long-term exposure to environmental and dietary carcinogens.
Highlights
Breast cancer is the most common type of cancer and second leading cause of cancer-related death among women in North America and Europe [1,2]
We first used a comet assay to measure the ability of these carcinogens to induce cellular DNA damage after one exposure, which is essential for the induction of cellular carcinogenesis [37]
Blockage of the ERK pathway or ROS production significantly reduced NNK and B[a]P (NB), PhIP, and NBP-induced DNA damage (Figure 1A). These results indicate that co-exposure to NB and PhIP was more potent than either was alone to induce DNA damage for induction of cellular carcinogenesis, and the ERK pathway and ROS production are required for this process
Summary
Breast cancer is the most common type of cancer and second leading cause of cancer-related death among women in North America and Europe [1,2]. The constitutive biochemical endpoints of Ras-Erk-Nox pathway activation and ROS elevation were induced consistently with constitutive cellular endpoints and may play important roles in maintaining cancer-associated properties in NBP-exposed cells.
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