# Suppression of progesterone receptor signaling by heavy metals promotes tamoxifen resistance and metastasis or ER+ breast cancer

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $453,805

## 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
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.

## Key facts

- **NIH application ID:** 10973137
- **Project number:** 1R01ES035353-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Marcelo G. Bonini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $453,805
- **Award type:** 1
- **Project period:** 2024-06-24 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10973137

## Citation

> US National Institutes of Health, RePORTER application 10973137, Suppression of progesterone receptor signaling by heavy metals promotes tamoxifen resistance and metastasis or ER+ breast cancer (1R01ES035353-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10973137. Licensed CC0.

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