# Obesity Increases Breast Cancer Penetrance in BRCA Mutation Carriers: A Role for Local and Systemic Factors

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $495,715

## Abstract

PROJECT SUMMARY
Mutant BRCA1 and BRCA2 DNA repair enzymes are causally linked to an increased risk of breast and ovarian
cancers. Recent evidence suggests that cancers occur at these hormone-sensitive sites, at least in part, due to
the pro-proliferative and mutagenic effects of estrogens. We reported that women who are obese have elevated
levels of aromatase, the rate-limiting enzyme for estrogen production, in inflamed breast adipose tissue. This
would be predicted to lead to increased local production of estrogen and may explain why obese post-
menopausal women are at increased risk of developing hormone receptor-positive breast cancer. Obesity has
been reported to increase the penetrance of breast cancer in BRCA1/2 mutation carriers. A major and potentially
transformative research challenge is determining whether our discovery of the obesity-inflammation-aromatase
link is important in the pathogenesis of breast cancer in BRCA1/2 mutation carriers. We now have possibly field-
changing preliminary data which suggest that acquired characteristics, such as obesity and adipose
inflammation, are associated with increased expression of aromatase in breast adipose stromal cells (ASCs)
and an associated increase in DNA damage in the normal breast epithelium of BRCA mutation carriers. In this
proposal, we will test the hypothesis that obesity, and associated breast white adipose tissue inflammation
(WATi), will increase breast cancer penetrance in BRCA mutation carriers via local and systemic effects,
including higher estrogen and insulin levels, that will lead to DNA damage in the breast epithelium and increase
tumor burden. This hypothesis will be tested by first investigating whether an association exists between obesity,
breast WATi and increased levels of systemic factors (e.g., estrogens, insulin, leptin, IL-6) in BRCA1/2 mutation
carriers (Aim 1). Then, we will assess correlations between body mass index (BMI), breast WATi, estrogens
and DNA damage in normal appearing breast epithelium (Aim 2). Given the importance of estrogens in the
pathogenesis of hereditary breast cancer, we will next characterize mechanisms of aromatase regulation in
breast adipose stromal cells of BRCA mutation carriers (Aim 3). Finally, we will utilize mouse models to
determine whether suppressing estrogen biosynthesis can reduce mammary gland DNA damage and increase
tumor latency, while also exploring whether a lifestyle intervention, i.e. reduction in caloric intake, or
pharmacological intervention, i.e. use of the anti-diabetic drug metformin, can prevent these cancer-promoting
changes (Aim 4). By focusing on the potential link between estrogen, DNA damage and breast cancer, this
study promises to provide insights into why obesity increases the penetrance of breast cancer in BRCA1/2
mutation carriers. Importantly, results in this high risk population could prove relevant for understanding the
mechanisms underlying the obesity-cancer connection for sporadic breast cance...

## Key facts

- **NIH application ID:** 10132182
- **Project number:** 5R01CA215797-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Kristy A. Brown
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $495,715
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132182

## Citation

> US National Institutes of Health, RePORTER application 10132182, Obesity Increases Breast Cancer Penetrance in BRCA Mutation Carriers: A Role for Local and Systemic Factors (5R01CA215797-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10132182. Licensed CC0.

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