# Unraveling the molecular link between heavy metal exposure and triple negative breast cancer

> **NIH NIH K99** · UNIVERSITY OF LOUISVILLE · 2024 · $124,087

## Abstract

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that lacks targeted therapies.
Individuals with Breast Cancer 1 (BRCA1) gene mutations have a significantly higher risk of developing TNBC
in their lifetimes compared to the rest of the population. TNBC disproportionately affects young Black women
and the mortality rate from TNBC is significantly higher among Black women. Although TNBC incidence is
higher in Black women compared to other groups, the incidence of germline BRCA1 mutations is significantly
lower in Black women, highlighting the need to pinpoint additional factors responsible for TNBC disparities.
Residential segregation created and perpetuated by discriminatory housing practices has led to predominantly
Black communities being located in close proximity to industrial sites, including Superfund sites, that are
commonly contaminated with heavy metals including cadmium (Cd). Cd is a heavy metal group 1 carcinogen
that has a long biological half-life in the human body. Epidemiological studies demonstrate that Cd exposure
increases breast cancer risk and in vitro studies determined that Cd exposure promotes TNBC initiation in
normal human breast cells. Cd is known to displace zinc (Zn) from Zn coordinating proteins and several Zn
coordinating proteins are important for DNA double-strand break (DSB) repair including RAD50 and BRCA1.
Cd promotes higher levels of DSBs and sister chromatid exchanges indicative of DSB repair pathway
inhibition. Whether Cd promotes TNBC initiation and progression by disruption of DSB signaling and repair,
including direct inhibition of RAD50 or BRCA1, remains to be established. I hypothesize that Cd exposure
promotes TNBC initiation and progression by disruption of multilateral DSB signaling and repair. The
experiments proposed to test this hypothesis will be conducted in two phases. During the mentored K99
phase, mass spectrometry, single-molecule imaging using isolated recombinant proteins and DNA curtain
assays, and CRISPR-based editing will be employed to determine how Cd directly targets DSB repair proteins
to disrupt DSB Repair pathway “choice”. While in the mentored phase, the candidate will take advantage of
career development resources made available by the University of Louisville Center for Integrative
Environmental Health Sciences and will apply research and career development skills to didactic lecturing,
mentoring, writing, and presentation opportunities. In the non-mentored R00 phase of the project, technical
skills gained from the K99 phase will be used for mechanistic studies to interrogate the role of Cd-induced
fusion genes in TNBC development (Aim 2). These experiments will provide data needed for initial
independent publications and preliminary data for R-series grants, and will establish an independent direction
for the candidate from her mentor.

## Key facts

- **NIH application ID:** 10865838
- **Project number:** 1K99ES036286-01
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Alexandra Nichole Nail
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $124,087
- **Award type:** 1
- **Project period:** 2024-08-16 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10865838

## Citation

> US National Institutes of Health, RePORTER application 10865838, Unraveling the molecular link between heavy metal exposure and triple negative breast cancer (1K99ES036286-01). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10865838. Licensed CC0.

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