Role of HMGCS2-Medicated Ketogenesis in Breast Epithelial-Stromal Interaction

The breast microenvironment plays an important role in cancer progression through the interaction between epithelial and stromal cells. Cancer stromal cells may function as regulatory cells to provide high-energy mitochondrial fuels through ketogenesis, and promote reverse Warburg effect in tumor cells that converts ketone bodies to acetyl-CoA for the TCA cycle. Thus, the coupling of ketogenesis and ketone body re-utilization is important to drive oxidative phosphorylation to fuel anabolic tumor growth under nutrients starvation and hypoxia conditions. Based on our preliminary findings of heterogeneous expression of mitochondrial HMG-CoA synthase (HMGCS2), the rate-limiting enzyme of ketogenic pathway, in breast cancer tissues and cell lines, we hypothesize that ketone bodies can be generated in stromal cells and in HMGCS2+ tumor cells, which in turn promotes tumor growth by re-utilization of ketone bodies in HMGCS2- tumor cells. We will set up a co-culture system of tumor cells and fibroblasts to determine whether HMGCS2-mediated ketogenesis promotes tumor cell proliferation and invasion, and then further explore signaling pathways involved in stromal-epithelial interaction by suppressing ketogenesis using HMGCS2-siRNA or metabolism-inhibitory compounds. We believe this study will lead to finding a new way to cut lipid metabolism-derived nutrients and energy supplies and suppress tumor growth.