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

"Mechanistic role of obesity in benzo(a)pyrene-initiated cancer," is an R01-funded research project focused on a surprising mechanistic link between visceral adipose tissue (VAT) and increased vulnerability of mammary epithelial cells to the Group I carcinogen benzo(a)pyrene (BaP). The project stems from discovery that secretions from VAT induce the aryl hydrocarbon receptor (AhR) protein in mammary epithelial cells, and that AhR upregulation is observed in mammary tissues of mice fed a high-fat diet. Because AhR expression and transcription contribute to multiple stages of malignant transformation and are known to be upregulated in human breast cancer, identifying the signals that drive AhR induction in breast carcinogenesis addresses a major gap in the field. Preliminary data indicate that factors secreted from VAT—including fibroblast growth factor-2 (FGF2) synergize with BaP to cause DNA damage and accelerated transformation of human mammary epithelial cells, and that AhR functions as a critical control point for BaP bioactivation in this synergistic process.

The central hypothesis is that factors released from human VAT potentiate BaP metabolism by inducing AhR, producing increased carcinogenic metabolites (for example, BPDE) and consequent DNA damage that contribute to malignant transformation of human mammary epithelial cells. To test this, the project pursues two specific aims. Aim 1 will determine how VAT-derived factors impact BaP metabolism and DNA damage in vitro, and will characterize the components of VAT responsible for effects on BaP metabolism and AhR induction. Aim 2 will assess, 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 BaP exposures. Across both aims, the investigators will probe the role of FGFR1 signaling the primary receptor for FGF2—on AhR activation and BaP metabolism, employing a FGFR1 inhibitor and a novel orthotopic model of FGFR1-driven mammary tumorigenesis.

Methodologically, the research integrates in vitro assays of BaP metabolism and DNA damage with in vivo models of diet-induced AhR induction and tumorigenesis, and employs a novel multiphoton imaging approach to analyze BaP metabolites. Expected outcomes include identification of specific mechanisms and metabolic pathways by which BaP interacts with VAT-derived factors to promote DNA damage and breast cancer and clarification of FGFR1 signaling's role in AhR activation and BaP bioactivation. By elucidating the unexpected connection between visceral adipose tissue secretions and BaP bioactivation, this work aims to advance understanding of how obesity increases breast cancer risk and to reveal potential molecular targets for preventing or mitigating carcinogen-driven breast tumorigenesis.