title: Weight Loss Reversed Obesity-Induced HGF/c-Met Pathway and Basal-Like Breast Cancer Progression.
abstract: Epidemiologic studies demonstrate that obesity is associated with an aggressive subtype of breast cancer called basal-like breast cancer (BBC). Using the C3(1)-TAg murine model of BBC, we previously demonstrated that mice displayed an early onset of tumors when fed obesogenic diets in the adult window of susceptibility. Obesity was also shown to elevate mammary gland expression and activation of hepatocyte growth factor (HGF)/c-Met compared to lean controls, a pro-tumorigenic pathway associated with BBC in patients. Epidemiologic studies estimate that weight loss could prevent a large proportion of BBC. We sought to investigate whether weight loss in adulthood prior to tumor onset would protect mice from accelerated tumorigenesis observed in obese mice. Using a life-long model of obesity, C3(1)-TAg mice were weaned onto and maintained on an obesogenic high-fat diet. Obese mice displayed significant elevations in tumor progression, but not latency or burden. Tumor progression was significantly reversed when obese mice were induced to lose weight by switching to a control low-fat diet prior to tumor onset compared to mice maintained on obesogenic diet. We investigated the HGF/c-Met pathway known to regulate tumorigenesis. Importantly, HGF/c-Met expression in normal mammary glands and c-Met in tumors was elevated with obesity and was significantly reversed with weight loss. Changes in tumor growth could not be explained by measures of HGF action including phospho-AKT or phospho-S6. Other mediators associated with oncogenesis such as hyperinsulinemia and a high leptin:adiponectin ratio were elevated by obesity and reduced with weight loss. In sum, weight loss significantly blunted the obesity-responsive pro-tumorigenic HGF/c-Met pathway and improved several metabolic risk factors associated with BBC, which together may have contributed to the dramatic reversal of obesity-driven tumor progression. Future research aims to evaluate the role of obesity and the HGF/c-Met pathway in basal-like breast cancer progression.
authors: Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA ; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA.
authors: Sneha
authors: S
authors: Sundaram
authors: Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA.
authors: Trinh L
authors: TL
authors: Le
authors: Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA.
authors: Luma
authors: L
authors: Essaid
authors: Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA.
authors: Alex J
authors: AJ
authors: Freemerman
authors: Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA.
authors: Megan J
authors: MJ
authors: Huang
authors: Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA ; UNC Nutrition Obesity Research Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA ; Department of Medicine, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA.
authors: Joseph A
authors: JA
authors: Galanko
authors: Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA.
authors: Kirk K
authors: KK
authors: McNaughton
authors: Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA ; Mouse Phase I Unit, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA.
authors: Katharine M
authors: KM
authors: Bendt
authors: Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA ; Mouse Phase I Unit, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA.
authors: David B
authors: DB
authors: Darr
authors: Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA ; UNC Nutrition Obesity Research Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA ; Department of Epidemiology, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA ; Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA.
authors: Melissa A
authors: MA
authors: Troester
authors: Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA ; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA ; UNC Nutrition Obesity Research Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA ; Department of Medicine, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA.
authors: Liza
authors: L
authors: Makowski
keywords: BMI; adiponectin; genetically engineered mouse model; high-fat diet; leptin; microenvironment; obese; triple-negative