University of Kentucky Center for Cancer and Metabolism (Pilot Project - Dr. Yadi Wu)

Basal-like breast cancer (BLBC) is a devastating form with limited therapeutic options. Lipids provide energy that contributes to proliferation and metastasis through fatty acid oxidation (FAO) and subsequent oxidative phosphorylation. FAO is critical for BLBC cell metabolism and contributes to cell proliferation and metastasis, particularly under conditions of nutrient stress. However, how FAO is regulated in BLBC remains elusive. We found that EBF1 is highly expressed in BLBC. Loss of EBF1 expression results in a dramatic decrease in the expression of ACAA2, a key enzyme of FAO. In addition, silencing EBF1 expression leads to triacylglycerides accumulation and lipid drop abundance in BLBC, suggesting a role of EBF1 in regulating cellular lipid metabolism. Based on these preliminary data, we speculate that EBF1 plays a critical role in regulating lipid metabolism by stimulating FAO through increasing ACAA2 expression, and loss of EBF1 expression inhibits BLBC progression including cell proliferation and metastasis as the result of lipid metabolic reprogramming. Our strategy will be to first delineate the functional importance of EBF1-mediated regulation of FAO in BLBC cells (Aim 1); then elucidate the regulatory mechanism of ACAA2 by EBF1 in BLBC cells (Aim 2). The knowledge gained from these studies will increase our fundamental understanding about biologic relationship between lipid metabolic reprogramming and BLBC progression. Our work also reveals a pivotal function for the EBF1 in BLBC and suggests that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer. We will submit a competitive R01 grant with the data collected from this project.