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.