Breast cancer is the deadliest cancer amongst women globally, with metastatic breast cancer being particularly deadly. Pyruvate carboxylase (PC) catalyzes the conversion of pyruvate to oxaloacetate for anaplerotic refilling of TCA cycle intermediates, feeding numerous energetic and biosynthetic pathways. Upregulation of PC is an important contributor to metabolic reprogramming and aggressiveness in metastatic breast cancer. Less understood, however, is the effects of PC expression on metabolic reprogramming and the TME in primary tumors. In this study, we investigate whether suppression of PC alters metabolism and drives microenvironmental adaptation in a primary tumor model of breast cancer. PC knockdown resulted in increased lactate production with a decrease in mitochondrial respiration, suggesting that diminished PC-mediated anaplerosis alters carbon utilization and contributes to metabolic reprogramming. Suppression of PC also resulted in tumors with distinct transcriptomic profiles versus control, with signatures of immune responses diminished in response to loss of PC. As lactate is a profound immunosuppressive signaling molecule in the TME, it may be a driver of TME immunosuppression in response to PC suppression. We conclude that PC knockdown promotes a metabolically altered tumor microenvironment associated with immunosuppression and tumor growth.Bachelor of Scienc
