| The American Cancer Society estimates that one in nine women in the United States will be diagnosed with breast cancer in their lifetime, with up to 45,000 deaths occurring from the disease each year. Epidemiological studies have identified a number of nutritional, social and genetic risk factors correlated with an increased risk in breast cancer. However, because of the large number of undefined causes, there has been interest in the hypothesis that environmental contaminants play a causative role. Polycyclic aromatic hydrocarbons, (PAHs) are one class of environmental pollutants that may contribute to human breast cancer. PAHs, such as benzo(a)pyrene (BaP), are widespread environmental contaminants formed through the combustion of fossil fuels, cooking of meats, and combustion of other organic matter. This laboratory has found that this chemical class of known rodent mammary carcinogens mimic growth factor signaling in human mammary epithelial cells (HMEC) leading to increased cell proliferation and survival. The specific mechanism by which BaP produced these effects in mammary epithelial cells is unknown, and was the key question addressed in this research.; The biological effects of BaP exposure are likely due to its conversion into more reactive metabolites. Here, we demonstrated that the redox-cycling BaP-quinones (BPQs), produced reactive oxygen species (ROS) in MCF-10A cells, which led to transactivation of the epidermal growth factor (EGF) receptor and increased cell survival under EGF deficient conditions. Genetic and pharmacological approaches to reduce intracellular ROS were protective against these effects, and suggested that hydrogen peroxide produced during redox-cycling was necessary for activation of the EGF receptor (EGFR). Another class of BaP metabolites, a DNA reactive and electrophilic epoxide (e.g. BaP-diol epoxide, BPDE), was also found to activate the EGFR pathway. BPDE treatment led to arrest of the cell cycle and the induction of apoptosis in HMECs. However, concurrent activation of the EGFR was found to be protective against apoptosis, suggesting a possible mechanism by which BPDE can act as a tumor promoter. Therefore, the activation of the EGFR by redox-cycling and electrophilic metabolites of BaP may represent an important avenue by which these compounds contribute to tumor promotion, and ultimately mammary carcinogenesis. |
