SUMMARY The central concept in this project is that exposure of existing estrogen receptor (ER) and progesterone (PR) positive (ER+/PR+) breast tumors to heavy metal pollutants promotes the emergence of tumor cells that lack PR expression and function. While ER+/PR+ breast cancer have excellent prognosis and respond well to treatments, ER+/PR- do not and often progress to high lethal recurrent metastatic disease. Hence, we propose that environmental arsenic, lead or mixtures of these metals present in particulate air pollution and water supplies, poses a grave risk for the successful treatment of women with ER+/PR+ breast cancer via promoting the reprogramming of these tumors to ER+/PR- phenotypes. In addition, we found that phenotypic reprogramming by heavy metals involves changes in the cellular nuclear redox state. As reactive oxygen species (ROS) increase in the nucleus, vastly because of heavy-metal induced mitochondrial dysfunction, progesterone receptor gene expression is suppressed unleashing phenotypic reprogramming. We also found that quenching these ROS at the origin (mitochondria) or the nucleus (site of activity) reverses the suppression of PR expression by iAs and Pb and to a large extent resensitizes metal-transformed breast cancer cells to the anti-neoplastic action of first line selective estrogen receptor modulators, often the most accessible therapy for low income and minority populations. Since, we now have FDA-approved, as well as, novel proprietary compounds to suppress nuclear ROS in tumor cells, this strategy may lead to much needed adjuvant therapies to mitigate some of the most devastating health effects of heavy metal contaminants affecting most heavily low income and minority breast cancer patients. Therefore the goals of this project are: 1) Determine how nuclear ROS-driven epigenetic reprogramming impacts ER+/PR+ tumor transitions to treatment refractory ER+/PR- phenotypes; 2) Determine if suppressing ROS in the nucleus restores treatment effectiveness in xenograft tumor models of metal-transformed cells; 3) Determine if FDA-approved pharmacologic mitochondrial ROS scavengers are effective in resensitizing metal-transformed tumor cells to chemotherapy.