Chronic exposure to combined carcinogens enhances breast cell carcinogenesis with mesenchymal and stem-like cell properties.
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.
Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, United States of America; Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, Tennessee, United States of America.
Lenora Ann
LA
Pluchino
Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, United States of America; Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, Tennessee, United States of America.
Hwa-Chain Robert
HC
Wang
D001564:Benzo(a)pyrene / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism*; D063646:Carcinogenesis / Q000187:drug effects* / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology*; D004249:DNA Damage; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D061986:MCF-7 Cells; D019255:NADPH Oxidases / Q000378:metabolism; D009602:Nitrosamines / Q000494:pharmacology; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
D002273:Carcinogens; D007093:Imidazoles; D009602:Nitrosamines; D017382:Reactive Oxygen Species; D001564:Benzo(a)pyrene; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins