# Arsenic suppresses progesterone receptor signaling and promotes tamoxifen resistance and metastasis of ER+ breast cancer

> **NIH NIH R56** · NORTHWESTERN UNIVERSITY · 2022 · $150,000

## Abstract

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
highly lethal recurrent metastatic disease. Hence, we propose that environmental arsenic,
cadmium, 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 in the nucleus (site of action) reverses the suppression of PR expression by iAs,
Cd 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 disproportionately affecting 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
SERMs. We propose that finding pharmacologic ways to mitigate some ofthe detrimental health
effects of exposures to heavy metals may be an urgent short term solution to reduce
environmental health disparities.

## Key facts

- **NIH application ID:** 10662054
- **Project number:** 1R56ES033398-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Marcelo G. Bonini
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $150,000
- **Award type:** 1
- **Project period:** 2022-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10662054

## Citation

> US National Institutes of Health, RePORTER application 10662054, Arsenic suppresses progesterone receptor signaling and promotes tamoxifen resistance and metastasis of ER+ breast cancer (1R56ES033398-01A1). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/10662054. Licensed CC0.

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