Inflammatory Cytokines Link Obesity and Breast Cancer

Abstract

The risk of postmenopausal breast cancer is significantly increased by obesity. Further, low grade chronic inflammation, a hallmark of obesity, can contribute to detrimental health effects including high cancer incidence. Our goal is to understand the molecular basis for obesity-breast cancer interactions and dissect the role of inflammatory mediators secreted by adipocytes and breast cancer cells. Accordingly, we developed a three-dimensional (3D) coculture system to facilitate direct cell-cell interactions and also performed media transfer from adipocyte cultures to growing breast cell cultures. The co-culture system will facilitate both adipocyte and breast cell growth in an environment closely mimicking in-vivo tumor microenvironment. Co-cultures of human primary adipocytes obtained from lean and obese women with MCF10A, MCF7 and MDAMB231 breast cells (non-cancerous epithelial cells, cancerous and invasive breast cancer cells, respectively), led to cell type specific changes in secretion of several pro-inflammatory cytokines, such as IL-6 and TNFα, compared to monocultures. Regulation of cytokine secretion of breast cells by adipocytes and vice versa indicates the two-way communication between breast cells and adipocytes. Further, 3D co-culture and adipocyte conditioned media transfer experiments demonstrated that obese adipocytederived conditioned media can promote higher growth of breast cancer cells compared to that from lean adipocytes. Moreover, obese adipocyte conditioned media increased the activation of nuclear factor-κB (NF-κB) family members in breast cells, compared to lean adipocyte-derived media. Our results provide a novel model system to study adipocytebreast cancer cell interactions which may underlie the link between breast cancer and obesity and also demonstrate that inflammatory cytokines and other secreted factors are important in this interaction.