The purpose of the present application is to generate the initial data on the plausible role that local breast adipose tissue may have in breast cancer progression in conditions of obesity/overweight. To do this, we will use diet-induced obesity mouse models of breast cancer. This work is a natural complement and extension of our ongoing NIH-funded work. Most studies linking obesity and cancer have focused on the systemic effects of adiposity. Particularly in breast cancer, little attention has been paid to whether obesity also promotes this disease through its effect on local adipose tissue inflammation and innate immune signaling in the breast- where cancer occurs. We propose that in conditions of obesity/overweight the local adipose tissue in the breast becomes inflammatory and contributes to cancer development in great part by recruiting larger numbers of tumor-promoting inflammatory macrophages to the breast tumor microenvironment. We will use an innovative experimental design to examine our hypothesis in diet-induced obese mice. We will gauge breast adipose tissue's capacity to promote tumor development using two other well-known fat depots as reference: visceral and subcutaneous fat depots, which exhibit high and low degrees of inflammation, respectively. To do this, we will analyze tumor progression, macrophage recruitment and production of inflammatory molecules in tumors arising from tumor cells implanted on these fat locations. Finally, we will use a novel compound belonging to a new family of small molecules discovered by our team. These molecules - termed leukadherins - reduce inflammation via activation of Mac-1 integrin. We will use Leukadherin-1 (LA-1), the most potent of the leukadherins, in an in vivo setting to examine its impact on tumor progression and macrophage recruitment. For this, we will treat obese and lean tumor-bearing mice with increasing doses of this compound. Also, we will in vitro pre-treat macrophages with different concentrations of LA-1 to determine whether this compound modulates macrophage's inflammatory signaling pathways and expression of inflammatory molecules. We envision that results from the present proposal will enable us to reveal the existence of a role for local breast adiposity and related molecules in obesity. Importantly, our work will also serve as means to assess the effect of these novel anti-inflammatory compounds in the control of breast cancer. A high-fat diet, overweight and reduced physical activity are common lifestyle aspects among African American and Latina women that increase cancer risk~ these minority women also exhibit more aggressive breast cancers with less favorable prognosis. The experiments proposed in this application address in an innovative fashion the nature and control of breast adipose tissue inflammation and its impact in breast cancer within obesity. There is an urgent need to build up studies to better understand the biology of cancers across ethnicities, and to develop tools that will more accurately predict their prognosis and design their customized treatment strategies.
The proposed studies will enable us to understand whether adipose tissue in the breast is inflammatory in obesity and plays a role in breast cancer development and macrophage recruitment to the tumor. Our work will corroborate if decreasing this inflammation using a novel compound may control breast cancer progression and make macrophages less in number and less inflammatory. Our research could lead to new ways of breast cancer prevention and/or therapeutic alternatives for overweight/obese women, especially African American and Latinas, characterized by high prevalence of obesity/overweight and more aggressive breast cancers with worst prognoses.