Supplement: Roles of RORalpha in Breast Cancer Development and Progression

The central hypothesis of our project is that downregulation of RORá in non-polarized breast cancer cells increased ROS generation in mitochondria, thereby inducing NF-êB and macrophage infiltration. We integrate a novel 3D co-culture system, high-throughput metabolic analysis, and global gene expression profiling to delineate mechanisms by which RORá inhibits ROS production and macrophage infiltration. The long-term goal of this proposal is to define the impact of the RORá/ROS axis in mediating mammary epithelial cell-macrophage crosstalk and in regulating breast cancer progression. We have proposed following specific aims to test the hypothesis: Aim 1. To elucidate the molecular mechanisms by which RORá reduces ROS levels and NF-êB activity in polarized mammary epithelial cells; Aim 2. To determine how reduced RORá expression in non-polarized breast cancer cells induces macrophage infiltration and M2 polarization; Aim 3. Define the impact of RORá in suppressing breast cancer formation and metastasis.