# Mechanistic role of obesity in benzo(a)pyrene-initiated cancer

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2020 · $403,429

## Abstract

Project Summary
This R01 is about our discovery of a surprising and unexpected way in which adipose tissue increases the
vulnerability of mammary epithelial cells to benzo(a)pyrene (BaP), a Group I-classified carcinogen, by inducing
the aryl hydrocarbon receptor (AhR) protein. Upregulation of AhR expression and transcription is important in
several, if not all, stages of malignant transformation. In particular, AhR is upregulated in human breast cancer.
A major gap in AhR research is the nature of the signals that drive AhR induction and activation in breast
carcinogenesis. Until now, no one might have expected that in the search for the unknown activators and
inducers of AhR, that secretions from visceral adipose tissue (VAT) would be among them. Remarkably, our
data shows that factors secreted from VAT can induce AhR in mammary epithelial cells, and AhR is also induced
in mammary tissues of mice fed a high-fat diet. Our preliminary data also strongly suggest: 1) BaP and secretions
from VAT, such as fibroblast growth factor-2 (FGF2), synergize to cause DNA damage and accelerated
transformation of human mammary epithelial cells; and 2) AhR is a critical control point for BaP bioactivation in
this synergistic process. Our central hypothesis is that factors secreted from human VAT will potentiate BaP
metabolism by inducing AhR, resulting in increased carcinogenic metabolites (e.g. BPDE) and DNA damage,
two well-known contributors to malignant transformation of human mammary epithelial cells. We will test this
hypothesis in connection with human breast cancer. In aim 1, we will determine the impact of factors released
from VAT on BaP metabolism and DNA damage in vitro. We will also determine what is in VAT that effects BaP
metabolism and induces AhR. In aim 2, we will determine for the first time in vivo the impact of high-fat diet
feeding on AhR-mediated BaP metabolism, DNA damage and mammary tumorigenesis using both acute and
chronic exposures to BaP. For both aims, we will determine the role of FGFR1 signaling, the primary receptor
for FGF2, on the AhR activation and metabolism of BaP using a FGFR1 inhibitor and a novel orthotopic model
of FGFR1-driven mammary tumorigenesis. The expected outcomes of this research will be to identify the
mechanisms and metabolic pathways by which BaP interacts with factors released from VAT in promoting DNA
damage and breast cancer. BaP metabolites will be analyzed using a novel multiphoton imaging approach.
Elucidating the unexpected and surprising connection between factors from human visceral adipose tissues and
the bioactivation benzo(a)pyrene (BaP) will be a major advance in understanding why obesity heightens the risk
of breast cancer.

## Key facts

- **NIH application ID:** 9971027
- **Project number:** 1R01ES030695-01A1
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Jamie J Bernard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,429
- **Award type:** 1
- **Project period:** 2020-07-13 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971027

## Citation

> US National Institutes of Health, RePORTER application 9971027, Mechanistic role of obesity in benzo(a)pyrene-initiated cancer (1R01ES030695-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9971027. Licensed CC0.

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