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A BET Bromodomain Inhibitor Suppresses Adiposity-Associated Malignant Transformation
Debrup Chakraborty1, Vanessa Benham1, Vladislav Jdanov1
1Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
Cancer Prevention Research (Philadelphia, Pa.)
|December 17, 2017
Summary
Obesity-linked visceral adipose tissue (VAT) and fibroblast growth factor 2 (FGF2) promote cancer. The bromodomain inhibitor I-BET-762 (I-BET) effectively prevents this malignant transformation by inhibiting c-Myc expression.
Area of Science:
- Oncology
- Metabolic Syndrome
- Cancer Prevention
Background:
- Obesity is linked to nearly half a million new cancer cases annually.
- Visceral adipose tissue (VAT) and high-fat diets (HFD) are implicated in increasing cancer risk.
- VAT-derived fibroblast growth factor 2 (FGF2) stimulates malignant epithelial cell transformation.
Purpose of the Study:
- To explore mechanism-based strategies for preventing VAT-enhanced tumorigenesis.
- To investigate the chemopreventive activity of bromodomain inhibitors, specifically I-BET-762 (I-BET).
- To test the hypothesis that I-BET prevents malignant transformation driven by VAT and FGF2.
Main Methods:
- Utilized in vitro models of VAT-stimulated epithelial cell transformation.
- Employed in vivo models of FGF2-stimulated tumor formation in mice.
- Assessed nuclear c-Myc expression in mice with visceral adiposity and epithelial cell lines.
Main Results:
- I-BET significantly attenuated VAT and FGF2-stimulated malignant transformation.
- I-BET inhibited VAT-induced c-Myc protein expression in skin and breast epithelial cells.
- I-BET significantly reduced tumor growth in FGF2-treated mice.
Conclusions:
- Bromodomain inhibitor I-BET-762 demonstrates significant chemopreventive efficacy against VAT and FGF2-driven tumorigenesis.
- I-BET acts by inhibiting c-Myc expression, a key oncogene implicated in obesity-associated cancers.
- These findings support the potential of I-BET as a therapeutic agent for preventing obesity-related cancers.
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