Abstract 5292: Visceral adiposity-stimulated genotoxicity and malignant transformation of epithelial cells

Abstract

Abstract Obesity is a global epidemic with a predicted rate of 42% in the U.S.A by 2050. Epidemiologic studies show that obesity is a risk factor for developing cancer; however, the molecular mechanism has not been fully elucidated. Our published data demonstrate that fibroblast growth factor-2 (FGF2) released from fat cells (adipocytes) in the visceral adipose tissue (VAT) induces transformation/tumorigenicity in the skin and mammary epithelial cells. Specifically, FGF2 released from VAT stimulates epithelial cell growth in soft agar by inducing the proto-oncogene c-Myc. Growth in soft agar is a measure of transformation/tumorigenicity; neither transformation nor c-Myc induction in epithelial cells was reversible. c-Myc overexpression can initiate a process of genetic instability linked to tumor initiation. Our discovery of this novel direct path of VAT-stimulated tumorigenesis adds mechanistic insight to our earlier discovery that VAT secretions promote UVR-induced nonmelamoma skin cancer. The objective of our current study was to determine the mechanism by which FGF2 stimulates malignant transformation. We hypothesized that FGF2 from VAT induces c-Myc and subsequent genomic instability in epithelial cells, leading to increased carcinogenesis. To test hypothesis we generated a filtered conditioned-medium from the human VAT treated MCF-10A (mammary epithelial) and JB6 P+ (skin epithelial) cells and measured several downstream mediators of FGF2 and activation of FGFR-1 (FGF2 receptor). Following VAT treatment, epithelial cells demonstrated induced c-Myc protein expression along with ROS accumulation, elevated γ-H2AX foci, and increased micronucleus (MN) formation. We found that inhibition of c-Myc attenuated VAT-induced neoplastic transformation of MCF-10A and JB6 P+ cells, while constitutive activation of the c-Myc-induced spontaneous neoplastic transformation of JB6 P+ cells. Collectively, our data suggested FGF2 released from VAT interacts with FGFR-1 and activates c-Myc. The role of c-Myc in the formation of MN and DNA damage is under investigation. Determining the impact of excess VAT on cancer will lead to strategies to help prevent adiposity-associated cancers and identify individuals at risk for disease or individuals who may be susceptible to compounded genotoxicity due to DNA-damaging environmental exposures. Citation Format: Debrup Chakraborty, Vladislav Jdanov, Vanessa Benham, Blair Bullard, Jamie J. Bernard. Visceral adiposity-stimulated genotoxicity and malignant transformation of epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5292.