Obesity is associated with an aggressive subtype of breast cancer called basal-like breast cancer (BBC). Using C3(1)-TAg mice, a genetically engineered mouse model that resembles human BBC, we demonstrated that mice displayed increased tumor aggressiveness when fed obesogenic diets. Obesity induced in the adult window of susceptibility triggered early latency and elevated 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. HGF secretion was also increased from primary mammary fibroblasts isolated from normal mammary glands and tumors of obese mice compared to lean. Conditioned media from primary tumor fibroblasts from obese mice drove tumor cell proliferation compared to lean controls. In co-culture, neutralization of secreted HGF blunted tumor cell migration, further linking obesity-mediated HGF-dependent effects to in vitro measures of tumor aggressiveness. Using a more severe diet model, we exposed mice to a lifelong diet intervention - C3(1)-TAg mice were weaned onto and maintained on an obesogenic high fat diet. Obese mice displayed significant elevations in tumor progression. 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 the accelerated tumorigenesis observed in obese mice. Indeed, 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. Obesity-elevated HGF/c-Met expression in normal mammary glands and c-Met in tumors was significantly reversed with weight loss. Other mediators associated with oncogenesis such as hyperinsulinemia and a high leptin/adiponectin ratio were also 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, the mammary microenvironment, and the HGF/c-Met pathway in basal-like cancer progression.

Learning Objective:

• After completing this activity the learner will be able to understand how obesity and weight loss affect the normal mammary gland and tumor in a murine model of basal like breast cancer.
• Links to human studies and ongoing outreach programs will be discussed.