# Mechanisms of obesity-induced breast epithelial cell DNA damage in BRCA mutation carriers

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $45,520

## Abstract

PROJECT SUMMARY/ABSTRACT
Obesity is a well-established risk factor for breast cancer. Obese women who carry a mutation in the DNA
repair enzymes BRCA1 and BRCA2 are at a greater risk of developing breast cancer compared with lean
BRCA mutation carriers. Molecular mechanisms that explain the increased penetrance of breast cancer in
obese BRCA mutation carriers are unknown. We have found that obesity is positively associated with DNA
damage in breast epithelial cells of BRCA mutation carriers. We also found that conditioned media (CM) from
obese breast adipose tissue stimulates DNA damage in association with elevated reactive oxygen species
(ROS) in breast epithelial cells. Furthermore, important for DNA repair genes are downregulated in breast
epithelial cells from obese women compared with lean women. This proposal will test the hypothesis that
elevation in obesity-induced DNA damage in breast epithelial cells is mediated by local adipose-derived factors
which 1) stimulate DNA damage via genotoxic effects of ROS and/or 2) reduce capacity for DNA repair.
Furthermore, carrying a BRCA mutation enhances this effect due to intrinsic defective DNA repair leading to
increased tumor penetrance. Therapies aimed at reducing adiposity may decrease DNA damage and
consequently decrease tumor burden. To test this hypothesis, the first aim of this proposal will identify the
adipose-derived factors that are responsible for driving DNA damage in breast epithelial cells and will
determine whether they act through mitochondrial ROS. The second aim will determine whether obesity is
associated with a defect in DNA repair. Finally, in the third aim, caloric restriction will be utilized to determine
whether reducing adiposity is sufficient to attenuate obesity-induced elevation in mammary gland DNA damage
leading to decreased tumor penetrance in obese mice carrying a Brca mutation. The identification of factors
responsible for causing DNA damage in BRCA mutation carriers and the molecular mechanisms involved will
highlight targets for therapeutic intervention in this at-risk population who are currently given few treatment
options beyond surgical intervention. This project will be undertaken in the laboratory of sponsor Dr. Kristy
Brown, a recognized expert in the field of obesity-related breast cancer, with the support of co-sponsor Dr.
Lewis Cantley, world expert in PI3K in the context of cell metabolism and cancer, including in BRCA mutation
carriers. The rich research environment at Weill Cornell Medical College and neighboring Rockefeller
University and Memorial Sloan Kettering Cancer Center, where cancer genetics and genomics expertise can
be found at every corner, is highly conducive to the exchange of ideas that will push this project forward.

## Key facts

- **NIH application ID:** 9971337
- **Project number:** 5F31CA236306-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Priya Bhardwaj
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971337

## Citation

> US National Institutes of Health, RePORTER application 9971337, Mechanisms of obesity-induced breast epithelial cell DNA damage in BRCA mutation carriers (5F31CA236306-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971337. Licensed CC0.

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