Abstract
Benzo[a]pyrene (B(a)P) is a major cancer-causing contaminant present in food such as cooked meats and cereals, and is ubiquitous in the environment in smoke derived from the combustion of organic material. Exposure to B(a)P is epidemiologically linked with the incidence of breast cancer. Although B(a)P is recognized as a complete genotoxic carcinogen, thought to act primarily via CYP-mediated metabolic activation to DNA-damaging species, there is also evidence that B(a)P exposure elicits other biological responses that promote development of the cancer phenotype. Here in mechanistic studies using human mammary cells MCF-7 and MDA-MB-231, we have explored mechanisms whereby B(a)P (10− 8 to 10− 5M) promotes inflammation pathways via TNF-α and NFκB leading to IL-6 upregulation, microRNA (Let7a, miR21 and miR29b) dysregulation and activation of VEGF. The miRNA dysregulation is associated with altered expression of inflammation mediators and increased migration and invasive potential of human mammary cancer cells. Our data suggest that mammary cell exposure to B(a)P results in perturbation of inflammation mediators and dysregulation of tumorigenic miRNAs, leading to an inflammation microenvironment that facilitates migration and invasion of mammary epithelial cells. These properties of B(a)P, together with its well-established metabolic activation to DNA-damaging species, offer mechanistic insights into its carcinogenic mode of action.
Highlights
Cigarette smoke, of which benzo[a]pyrene (B(a)P) is a constituent, has been shown to stimulate the production of inflammation cytokines in lungs (Lee et al 2012; Lin et al 2010; van der Vaart et al 2004) and smoking is linked with increased risk of breast cancer (Cui et al 2006)
We report that mammary cell exposure to B(a)P leads to altered expression of COX-2, TNF-α, vascular endothelial growth factor (VEGF), IL-6, and oncogenic miRNAs and collectively these interrelated events are consistent with B(a)P promoting an inflammation environment
The response to B(a)P was less pronounced in MCF-7 cells and statistical significance was only achieved at the highest concentration of B(a)P employed; there was a statistically significant trend detected for both COX-2 and TNF-α (Fig. 1a, c)
Summary
Of which benzo[a]pyrene (B(a)P) is a constituent, has been shown to stimulate the production of inflammation cytokines in lungs (Lee et al 2012; Lin et al 2010; van der Vaart et al 2004) and smoking is linked with increased risk of breast cancer (Cui et al 2006). Intake of processed meat, known to be contaminated with B(a)P, increases circulating inflammation biomarkers in women (Ley et al 2014) and consumption of a pro-inflammation diet can elevate the risk of breast cancer (Shivappa et al 2015). This epidemiological and clinical evidence strongly implicate cigarette smoke and consumption of processed meat being linked with the increased incidence of breast cancer. Metastasis and invasion are the life-threatening oncogenic events in terminal
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