The central concept in this project is that exposure of existing estrogen receptor (ER) and progesterone (PR) positive (ER+/PR+) breast tumors to inorganic arsenic (iAs) pollution 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. Hence, we propose that environmental arsenic, present in particulate air pollution and watersheds, poses a significant risk for the successful treatment of women with ER+/PR+ breast cancer via promoting the reprogramming of these tumors to a ER+/PR- phenotype. In addition, we found that phenotypic reprogramming by iAs involves changes in the cellular nuclear redox state. iAs increases reactive oxygen species (ROS) in the nucleus leading to transcriptomic changes enabling phenotypic reprogramming. The use of strategies to suppress nuclear ROS reversed the suppression of PR expression by iAs and to a large extent resensitized iAs-exposed breast cancer cells to the anti-neoplastic action of chemotherapeutics. Since, we now have compounds to suppress nuclear ROS specifically in tumors, this strategy may lead to novel and much needed adjuvant therapies to mitigate the effects of iAs in promoting breast cancer evolution to life threatening phenotypes. Therefore the goals of this project are: 1) Determine how ROS-driven structural chromatin changes occurring in iAs-exposed ER+/PR+ impact the transcriptome leading to phenotypic reprogramming; 2) Determine if suppressing ROS in the nucleus restores treatment effectiveness in xenograft tumor models of iAs-transformed cells; 3) Determine using tissues from available cohorts if levels of circulating heacy metals (and in particular iAs) correlate with increased risk of ER+/PR- tumors, treatment failure and reduced survival. In addition, test whether an innovative low cost device that enables self-sampling can be used to monitor environmental and occupational exposures to heavy metals in adults.
|Effective start/end date||9/15/22 → 8/31/23|
- National Institute of Environmental Health Sciences (1R56ES033398-01A1)
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