Roles of RORalpha in Breast Cancer Development and Progression

Tumor has been described as the wounds that do not heal. The two share some common features, such as loss of polarized tissue structure and chronic inflammation. We showed that disruption of tissue polarity induced macrophage infiltration. However, little is known of how disruption of epithelial cell polarity at early stage of breast cancer development induces macrophage infiltration. We have identified the RAR-related orphan nuclear receptor á (RORá) as a potent tumor suppressor by analyzing global gene expression profiles in polarized and non-polarized mammary epithelial cells. Our recent findings show that RORá inhibits ROS generation and macrophage infiltration in the syngeneic mouse mammary tumor model. These results suggest that RORá is a potent suppressor of macrophage infiltration in mammary epithelial cells. We found that knockdown of RORá significantly induced ROS production in mammary epithelial cells. Reactive oxygen species (ROS) are the driver of cancer progression and critical regulator of the NF-êB pathway. Based on these novel findings, the central hypothesis of our proposal 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 high-throughput metabolic analysis, novel 3D co-culture assay, 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 in mammary epithelial cells; Aim 2. To determine how reduced RORá expression in non-polarized breast cancer cells induces macrophage infiltration and differentiation; Aim 3. To define the roles of RORá in suppressing breast cancer development and progression in vivo. The proposed study is high impact for its inherent scientific importance and its translational potential. This study will elucidate the molecular mechanism by which disruption of tissue polarity induces macrophage infiltration/differentiation. Determining roles of RORá in reducing ROS generation and inhibiting NF-êB activation may identify a novel strategy to inhibit breast cancer development and progression.