Abstract P6-02-09: Role of HGF in obesity-associated tumorigenesis: C3(1)-Tag mice as a model for human basal-like breast cancer

Abstract

Obesity is associated with basal-like breast cancer (BBC), an aggressive breast cancer subtype. The objective of this study was to determine whether high fat diet-induced obesity promotes BBC onset in adulthood and to evaluate the role of stromal-epithelial interactions in obesity-associated tumorigenesis. Specifically, we hypothesized that hepatocyte growth factor (HGF) plays a promoting role in BBC, which tends to express the HGF receptor, c-Met. In C3(1)-Tag mice, a murine model of BBC, we demonstrate that obesity leads to a significant increase in HGF secretion and an associated decrease in tumor latency. By immunohistochemical analysis, normal mammary tissue exhibit obesity-induced hepatocyte growth factor (HGF) in stroma and corresponding epithelial expression of c-Met. HGF secretion was also increased in primary mammary fibroblasts isolated from normal mammary and tumors of obese mice compared to lean. These results show that diet-induced elevation of HGF expression is a stable phenotype, maintained after several passages and after removal of dietary stimulation. In cocultures, neutralization of HGF blunted tumor cell migration; further linking diet-mediated HGF-dependent effects in tumor aggressiveness. In sum, these results suggest that HGF plays an important role in obesity-associated carcinogenesis and raise the hypothesis that diet may affect lasting changes in stroma, potentially through epigenetic means. Understanding the effects of obesity on risk and progression is important given epidemiologic studies that imply half of BBC could be eliminated by reducing obesity. Our findings suggest the possibility that reducing obesity may be useful in preventing obesity-associated breast cancer mediated by the HGF/c-Met pathway. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-02-09.