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Cancer Prev Res (Phila). 2018 Mar;11(3):129-142. doi: 10.1158/1940-6207.CAPR-17-0262. Epub 2017 Dec 15.

A BET Bromodomain Inhibitor Suppresses Adiposity-Associated Malignant Transformation.

Author information

1
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
2
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan. jbernard@msu.edu.

Abstract

Almost half a million of all new cancers have been attributed to obesity and epidemiologic evidence implicates visceral adipose tissue (VAT) and high-fat diets (HFD) in increasing cancer risk. We demonstrated that VAT-derived fibroblast growth factor 2 (FGF2) from mice fed an HFD or obese individuals stimulates the malignant transformation of epithelial cells. Mechanism-based strategies to prevent this VAT-enhanced tumorigenesis have not been explored. Clinical studies have indicated that bromodomain inhibitors have considerable potential as therapeutic agents for cancer by inhibiting the activity of several oncogenes, including c-Myc; however, their chemopreventive activity is unknown. We show herein that mice with visceral adiposity have elevated nuclear c-Myc expression in their epidermis. We hypothesized that the bromodomain inhibitor I-BET-762 (I-BET) would have efficacy in the prevention of malignant transformation by VAT and FGF2. We tested this hypothesis using our novel models of VAT-stimulated transformation in vitro and FGF2- stimulated tumor formation in vivo We found that I-BET significantly attenuates VAT and FGF2-stimulated transformation and inhibits VAT-induced c-Myc protein expression in several skin and breast epithelial cell lines. Moreover, I-BET attenuated tumor growth significantly in FGF2-treated nude mice. Work is ongoing to determine the role of visceral adiposity in c-Myc activity in several tissues and determine the inhibitory effect of I-BET on VAT-promoted tumors in vivoCancer Prev Res; 11(3); 129-42. ©2017 AACRSee related editorial by Berger and Scacheri, p. 125.

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