Abstract IA45: Obesity and the microenvironment in basal-like breast cancer
Authors: Sundaram Sneha , Darr David B. , McNaughton Kirk K. , Galanko Joseph A. , Troester Melissa A. , Makowski Liza 
Published: October 2015

Obesity is associated with an aggressive subtype of breast cancer called basal-like breast cancer (BBC). BBC is a triple-negative subtype characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and type-2 human epidermal growth factor receptor (HER2) and as such, BBCs are a breast cancer subtype without a targeted therapy. BBC disproportionately affects young (&lt; 50 years old) and African-American women. Given that African-Americans experience higher rates of pubertal and adult obesity, gain more weight during and retain more weight after pregnancy, it is important to better understand the biological mechanisms by which obesity, a modifiable risk factor, increases the risk of 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. On 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. Elevated mammary gland expression and activation of hepatocyte growth factor (HGF)/c-Met pro-tumorigenic pathway associated with BBC in patients compared to lean controls. We saw obesity-induced activation of the HGF/cMet pathway in the normal mammary in C3(1)-TAg mice. Using a primary co-culture model to mimic the obese microenvironment, we demonstrated that HGF secretion was 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 and migration in an HGF-dependent manner. Epidemiologic studies estimate that weight loss could prevent a large proportion of BBC. We next 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. Importantly, 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 inhibition of the HGF/c-Met pathway in basal-like cancer progression. Improved understanding of biological mechanisms will yield prevention strategies to address racial disparities.

Citation Format: Sneha Sundaram, David B. Darr, Kirk K. McNaughton, Joseph A. Galanko, Melissa A. Troester, Liza Makowski. Obesity and the microenvironment in basal-like breast cancer. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr IA45.