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

Award Number: R01ES035353
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/24/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Environmental Health	000	2	2/11/2026	NON-COMPETING CONTINUATION	$0
2026	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Environmental Health	001	3	4/14/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $480,443 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Environmental Health	000	2	3/24/2025	NON-COMPETING CONTINUATION	$436,338
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Environmental Health	002	3	7/11/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$480,442
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Environmental Health	001	2	7/10/2025	NON-COMPETING CONTINUATION	-$436,337
														Subtotal = $480,443

Issue Date FY: 2024 ( Subtotal = $453,805 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Environmental Health	000	1	6/24/2024	NEW	$453,805
														Subtotal = $453,805

Grand Total All Awards = $934,248

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

Award Number: R01ES035353

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/24/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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