Assessment of Breast Cancer Development and Aggression with Heavy Metal Exposures in Illinois

Background: Heavy metals are ubiquitous in the environment and are naturally found throughout the ecosystem. They are non-biodegradable, persistent and bioaccumulate. In vitro and in vivo studies have demonstrated heavy metals bind to estrogen receptor alpha and mimic the effects of estrogen making them a potential risk factor for breast cancer subtype development. This dissertation examined associations between airborne heavy metal exposures with aggressive breast cancer characteristics and examined DNA methylation of cancer-specific genes as a potential intermediary. Methods: Data come from the Breast Cancer Care in Chicago study, a population-based study of non-Hispanic (nH) White, nH Black and Hispanic breast cancer patients (N=989). Using participant residential histories, we estimated fifteen-year chronic, airborne, residential exposures to eleven heavy metals based on data from the US Environmental Protection Agency’s National-scale Air Toxics Assessment. Bisulfate pyrosequencing was used to quantify promoter methylation of BRCA1, EGFR, GSTM2, RASSF1 and TFF1 in adjacent normal, in situ and invasive breast tissue components. Global methylation was quantified via Satellite 2 methylation. Markers of breast cancer aggression were estrogen receptor/progesterone receptor (ER/PR) negative status and high tumor grade. Results: Non-Hispanic black women were more likely to be diagnosed with ER/PR-negative and high grade tumors and were more likely to be exposed to greater concentrations of heavy metals. Increasing, chronic exposures to concentrations of antimony, arsenic, cobalt, manganese and selenium were associated with increased prevalence of ER/PR-negative and high grade tumors. Chronic exposure to antimony, cobalt, lead and manganese were associated with increased promoter methylation of GSTM2 in invasive breast tissue components. Finally, increased methylation of the GSTM2 promoter region across all tissue components was associated with increased prevalence of ER/PR-negative and high grade tumors. Conclusions: Exposure to airborne heavy metals may be etiologically involved in the development of aggressive breast cancer characteristics through their effects on gene-specific methylation of cancer-associated genes. GSTM2 is responsible for the detoxification of environmental pollutants and offers a potential mechanism to explain our findings. Long-term, low-dose exposures to airborne heavy metals affect large populations; therefore targeted remediation efforts may be a cost-effective approach to reducing breast cancer aggression racial disparities.