Obesity is associated with higher breast cancer mortality. The molecular interactions between fat and breast tissues are highly intricate. Invading breast cancer cells are surrounded by adipocytes (fat cells), which promote cancer aggressiveness in a process termed adipocyte-breast cancer crosstalk. Breast cancer cells cause adipocytes to undergo de-lipidation and overexpress pro-inflammatory proteins called cytokines and matrix metalloproteinases (MMPs). These altered adipocytes then increase the malignancy of breast cancer cells. Macrophages (immune cells) also secrete cytokines and upregulate MMPs. More macrophages infiltrate into breast tissue in obese human patients compared to lean patients but the roles of these macrophages in adipocyte-breast cancer interactions are poorly understood. Our goals are to investigate these complex biochemical interactions and identify novel therapeutic biomarkers for effective treatment of breast cancer.

The central hypothesis is that macrophages may promote obesity-linked inflammation and breast cancer progression in obese patients. We will construct a novel 3-dimensional human cell co-culture system mimicking in vivo human breast cancer microenvironment to investigate the effects of macrophages on adipocyte-breast cancer interaction. We hypothesize that macrophage secreted interleukin-6 and tumor necrosis factor-alpha will increase adipocyte de-lipidation. These cytokines can increase adipocyte de-lipidation in other tissues, and may drive the adipocytes-breast cancer crosstalk. We showed that introducing macrophage-conditioned media into this crosstalk increases cancer cell proliferation and mobility. We hypothesize that macrophages will increase MMP-3 and MMP-11 production by adipocytes that promote adipocyte de-lipidation and de-differentiation. We will investigate if breast cancer related adipocyte de-lipidation can be suppressed via inhibition of MMP activity. Synthetic small molecular enzyme inhibitors will be tested to evaluate their efficacy to block these proteinase activities and breast cancer invasion. Finding a way to break this obesity-inflammation-breast cancer vicious cycle may lead to better treatment strategies for obese breast cancer patients.