Developmental Exposures, Stem Cell Reprogramming, and Breast Cancer Disparities

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Abstract. This application is to renew R01ES028802, Dr. Colacino’s Outstanding New Environmental Scientist (ONES) award. The goal of this project is to define the impacts of chemical exposures on breast cancer disparities. There are profound breast cancer disparities by race. African American women are two to three times more likely to be diagnosed with the most aggressive subtype, triple negative, and 40% more likely to die of breast cancer. The etiological drivers of these disparities are complex and multifactorial. We have identified stark racial disparities in chemical biomarkers in US women across a multitude of toxicants. Our preliminary data show that many of these chemicals have breast cancer associated functional and molecular bioactivity at doses relevant to human exposure. Understanding how chemical exposure disparities impact aggressive breast cancer biology and breast cancer mortality would provide us with much needed strategies for precision prevention and identify new molecular targets for treatment. Aggressive breast cancers are characterized by the acquisition of the Hallmarks of Cancer, promoted by the environmental via the Key Characteristics of Carcinogens. Reflected in the 2022 updated Hallmarks, data from us and others shows that aggressive breast cancers acquire a “stem cell-like” phenotype through dysregulation of developmental pathways or the expansion of stem cells. Intriguingly, our preliminary data using high throughput transcriptomic profiling of 19 of these chemicals shows that multiple exposures, including p,p’-DDE and lead, induce phenotypic plasticity in non-transformed breast cells. Here, we will integrate human exposure data, publicly available toxicity data, and high throughput in vitro characterization of chemical effects in normal breast cells from diverse donors, with external validation in molecular epidemiology datasets. Based on our previous findings and preliminary data, our hypothesis is that these chemicals will promote cancer hallmarks and the acquisition of stemness at human relevant doses and will be associated with breast cancer mortality and aggressive breast cancer molecular profiles. Aim 1 will quantify dose-dependent functional and transcriptional effects of exposure disparity chemicals. Aim 2 will define impacts of exposure disparities chemicals on the acquisition of hybrid stem cell states. Aim 3 will quantify chemical exposure disparities in breast cancer mortality and outcomes. We propose an epidemiologically-informed precision toxicology approach that we expect will determine key chemical drivers of aggressive breast cancers and their molecular targets. Understanding how chemical exposures impact health disparities is urgently needed for new prevention and treatment strategies.