title: Reactive oxygen species-mediated breast cell carcinogenesis enhanced by multiple carcinogens and intervened by dietary ergosterol and mimosine.
abstract: Most breast cancers occur sporadically due to long-term exposure to low-dose carcinogens in the diet and the environment. Specifically, smoke, polluted air, and high-temperature cooked meats comprise multiple carcinogens, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), benzo[α]pyrene (B[α]P), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). We sought to determine if these carcinogens act together to induce breast cell carcinogenesis, and if so, whether noncytotoxic dietary agents could intervene. We demonstrated that coexposure to physiologically achievable doses of NNK, B[α]P, and PhIP (NBP) holistically enhanced initiation and progression of breast cell carcinogenesis. Reactive oxygen species (ROS) and activation of the ERK pathway were transiently induced by NBP in each exposure, and cross talk between reinforced ROS elevation and ERK activation played an essential role in increased DNA oxidation and damage. After cumulative exposures to NBP, this cross talk contributed to enhanced initiation of cellular carcinogenesis and led to enhanced acquisition of cancer-associated properties. Using NBP-induced transient changes, such as ROS elevation and ERK pathway activation, and cancer-associated properties as targeted endpoints, we revealed, for the first time, that two less-studied dietary compounds, ergosterol and mimosine, at physiologically achievable noncytotoxic levels, were highly effective in intervention of NBP-induced cellular carcinogenesis. Combined ergosterol and mimosine were more effective than individual agents in blocking NBP-induced transient endpoints, including ROS-mediated DNA oxidation, which accounted for their preventive ability to suppress progression of NBP-induced cellular carcinogenesis. Thus, dietary components, such as mushrooms containing ergosterol and legumes containing mimosine, should be considered for affordable prevention of sporadic breast cancer associated with long-term exposure to environmental and dietary carcinogens.
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA; Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, TN 37996, USA.
authors.forename: Lenora Ann
authors.initials: LA
authors.lastname: Pluchino
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA.
authors.forename: Amethyst Kar-Yin
authors.initials: AK
authors.lastname: Liu
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA; Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, TN 37996, USA. Electronic address: hcrwang@utk.edu.
authors.forename: Hwa-Chain Robert
authors.initials: HC
authors.lastname: Wang
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D001580:Benzopyrenes / Q000633:toxicity*; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D004875:Ergosterol / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000633:toxicity*; D020935:MAP Kinase Signaling System; D042361:Mammary Glands, Human / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008898:Mimosine / Q000494:pharmacology*; D009602:Nitrosamines / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001580:Benzopyrenes; D002273:Carcinogens; D007093:Imidazoles; D009602:Nitrosamines; D017382:Reactive Oxygen Species; D008898:Mimosine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D000444:Aldehyde Dehydrogenase; D048049:Extracellular Signal-Regulated MAP Kinases; D004875:Ergosterol
keywords: Antioxidants; Breast cell carcinogenesis; Carcinogens; Dietary prevention