# Environmental Arsenic in the Subtype Specification of Breast Cancer

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $356,423

## Abstract

ABSTRACT
Environmental inorganic arsenic (iAs) is a class I human carcinogen with established roles in
promoting skin, colon, bladder and kidney cancers. The role of iAs as a breast carcinogen is
less established although numerous studies have indicated that in cell cultures iAs promotes the
specification of breast cancer cells towards phenotypes that are estrogen receptor negative
which are more lethal as well as more challenging to treat. The molecular mechanisms involved
remain unknown. Our laboratory found that iAs promotes alterations in the metabolism of
mitochondrial reactive oxygen species (ROS) via inhibiting the tumor suppressor Sirtuin 3 which
leads to the accumulation of manganese superoxide dismutase (MnSOD) in an acetylated form
(MnSOD-Ac), increased reactive oxygen species (ROS) and the activation of hypoxia induced
factor 2α (HIF2α). The activation of HIF2α is a well-established mechanism of stem cell
reprogramming that has also been implicated in metastatic recurrence as well as treatment
failure in women with breast cancer. Hence, we propose that chronic iAs exposure is a risk
factor for the development of ER(-) breast cancer via a mechanism that involves MnSOD
acetylation and mitochondrial ROS. By extension, we propose that the MnSOD-Ac/HIF2α
molecular signature may identify women with breast cancer that have been exposed to iAs and
required personalized care for they are at increased risk of failing standard therapeutics. Also,
that the MnSOD-Ac/HIF2α may be targeted to improve therapy in these women. Our aims are
as follows: (1) determine if MnSOD-Ac reprograms tumor cell to stem-like (more aggressive)
phenotypes associated with chemoresistance and if targeting MnSOD-Ac reverses this effect.
(2) determine if low level iAs exposure in the drinking water transforms ER+ in situ xenograph
tumors developing in mice towards more pervasive phenotypes. (3) determine if there is an
association between exposure to iAs and breast cancer with a MnSOD-Ac, or MnSOD-ROS-
HIF2α molecular signature as well as if iAs exposure promotes chemoresistance or a
prevalence of aggressive ER(-) phenotypes.

## Key facts

- **NIH application ID:** 10488608
- **Project number:** 5R01ES028149-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Marcelo G. Bonini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $356,423
- **Award type:** 5
- **Project period:** 2020-06-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488608

## Citation

> US National Institutes of Health, RePORTER application 10488608, Environmental Arsenic in the Subtype Specification of Breast Cancer (5R01ES028149-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10488608. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*