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.

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Background: Epidemiologic studies demonstrate that obesity-associated basal-like breast cancer is an aggressive subtype and as a triple negative subtype, no targeted therapies are currently available. Basal-like breast cancer (BBC) is often diagnosed in young and African American women. Using a murine model of BBC, C3(1)-TAg, we previously reported that like humans, mice made obese in adulthood displayed an early onset of tumors. Obesity also elevated mammary gland expression and activation of the pro-tumorigenic hepatocyte growth factor (HGF) and its cognate receptor (c-Met) pathway compared to lean controls. We sought to investigate whether weight loss prior to tumor onset would protect mice from accelerated tumorigenesis and elevations in HGF/c-Met pathway. Methods: C3(1)-TAg mice were fed a high fat diet (60% kcal from fat) at weaning and became obese compared to control mice fed a low fat diet (10% kcal from fat). Weight loss was induced through a diet intervention: obese mice on 60% diet were switched to 10% at 10 weeks of age. Mice were monitored for fat mass accretion, tumor onset, and tumor progression. At sacrifice, various tissues were collected and plasma measures of cytokines and metabolic parameters were assessed. Immunohistochemical analyses for HGF, c-Met and F4/80 macrophage markers were performed. Results: C3(1)-TAg mice fed 60% diet displayed significant elevations in body weight and body fat composition which were reversed to control levels after two weeks after switching to 10% dietof weight loss. Tumor latency or burden were not altered but obesity dramatically regulated tumor aggressiveness. Obese C3(1)-TAg mice displayed significant elevations in tumor promotiongrowth, which were reversed to control levels when obese mice lost weight. Importantly, the HGF/c-Met axis was also elevated by obesity and reversed restored to control levels uponwith weight loss. Other obesity-associated parameters such as hyperinsulinemia and leptin/adiponectin ratio were elevated in obese mice and reduced with weight loss. Although systemic inflammatory cytokines were not significantly altered by obesity or weight loss, macrophage infiltration into the normal mammary gland was significantly elevated in obese mice with a decrease to control levels observed following weight loss. Conclusions: In sum, weight loss reversed obesity-driven tumor aggressiveness promotion and blunted the obesity-responsive pro-tumorigenic HGF/c-Met pathway, as well as improved several metabolic and inflammatory risk factors associated with BBC. Citation Format: Sneha Sundaram, Trinh Le, Luma Essaid, Kirk K. McNaughton, Katharine M. Bendt, David B. Darr, Melissa A. Troester, Liza Makowski. Weight loss prevents obesity-associated basal-like breast cancer progression: Role of hepatocyte growth factor/c-Met. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5040. doi:10.1158/1538-7445.AM2014-5040