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Abstract
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