# Evaluating the impact of obesity associated fatty acid metabolic dysregulation on breast cancer sensitivity to ferroptosis

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $14,797

## Abstract

Project Abstract
Breast cancer remains the second-leading cause of cancer-related death in the US. Obesity is an established
risk factor for several aggressive breast cancer subtypes, and is also associated with increased breast cancer
metastasis and mortality. On a mechanistic level, diet-induced obesity drives dysregulation of lipid metabolism
that results in greater extracellular fatty acid availability, providing a rich energy source for tumor proliferation
and migration. While this has been shown to increase the severity of breast cancer progression and metastasis,
the therapeutic potential of this metabolic relationship has not yet been investigated. Dependent upon fatty acid
availability and linked to metastatic progression of several cancer types, ferroptosis, a mechanism of cell death
caused by lipid peroxidation, serves as a targetable mediator between obesity, fatty acid metabolism, and breast
cancer progression. Our preliminary findings support the ferroptosis-metastasis link and suggest obesity-induced
dysregulation of fatty acid metabolism may exacerbate this relationship. This proposal will use murine models of
obesity and metastatic mammary cancer in concert with several advanced mechanistic approaches, including
lipidomic quantification of tumor and plasma as well as high-throughput RNA sequencing for assessing
transcriptional regulation of lipid metabolism in the primary and metastatic tumor microenvironment, to rigorously
test the hypothesis that dysregulation of fatty acid metabolism associated with obesity promotes sensitivity to
ferroptosis in murine models of TNBC. This hypothesis will be tested with two integrated specific aims:
Aim 1. Quantify the impact of obesity and ferroptosis induction on murine mammary tumor growth, metastasis,
and fatty acid metabolism in vivo. To isolate the effect of fatty acid availability from other components of the
tumor microenvironment, in vitro exposure to serum from control or DIO mice will be used to assess changes in
sensitivity to inhibition of xCT and GPX4 in TNBC.
Aim 2. Determine whether the enzyme pyruvate carboxylase (PC), uniquely involved in both fatty acid and
glutamate metabolism, protects against ferroptosis in obesity by assessing if suppression of PC promotes
sensitivity to ferroptosis in both primary and metastatic tumors of DIO mice. Transcriptional dysregulation of lipid
and glutamate metabolism in obese and control shPC TNBC tumors, comparing primary and metastatic tumors,
will be quantified via RNAseq.
This proposal aims to define molecular characteristics of fatty acid metabolism enriched in breast cancer of
patients with obesity to identify therapeutic targets that can decrease breast cancer mortality by limiting tumor
progression and metastasis. Combined with the exceptional training environment at UNC, comprehensive
mentoring from Dr. Hursting, and a focused training plan, this fellowship will provide a critical foundation for
developing my future career as an inde...

## Key facts

- **NIH application ID:** 11056676
- **Project number:** 5F31CA275336-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Emily Devericks
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $14,797
- **Award type:** 5
- **Project period:** 2023-09-12 → 2025-01-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11056676

## Citation

> US National Institutes of Health, RePORTER application 11056676, Evaluating the impact of obesity associated fatty acid metabolic dysregulation on breast cancer sensitivity to ferroptosis (5F31CA275336-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11056676. Licensed CC0.

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