Project Summary / Abstract Despite significant advances in treatment, women are still dying from breast cancer, particularly triple negative breast cancer (TNBC). More than 50% of women with TNBC have elevated circulating triglycerides (TGs), and these elevated levels are associated with reduced breast cancer survival. While the link between hypertriglyceridemia (HTG) and TNBC is well described in epidemiology studies, checking and treating TG levels in women with TNBCs are not part of standard clinical care. To understand the biological links between HTG and TNBC progression, we employ pre-clinical models of hypertriglyceridemia in isolation from other metabolic abnormalities. In our preliminary studies, we have found that the mice with HTG develop more rapid growth and metastasis in murine models of TNBC. The HTG mice demonstrated lipid profiles with elevated very low density lipoprotein (VLDL), and high circulating of phospholipids associated with elevated VLDL. Examining RNA sequencing gene expression, we found that a number of genes associated with cholesterol synthesis and peroxisome proliferator activated receptor (PPAR) signaling were downregulated in the TNBC from our HTG models, while cytoskeleton related genes were upregulated. As these gene expression changes have previously been related to hypoxia signatures, we examined lipid peroxidation products and found higher levels of lipid peroxidation sterols in the tumors from the HTG mice. In addition, we found increased phosphorylation of p42/44 mitogen activated protein kinase (MAPK) and epithelial to mesenchymal transition (EMT) markers. VLDL binds to the VLDL receptor (VLDLR), which is part of a breast cancer gene signature that is associated hypoxia and is highly expressed on the basal-like subtype of TNBC. High VLDLR expression in breast cancer has been associated with cancer metastasis, and its expression in basal-like TNBC is associated with a 50% decrease in recurrence free survival. Therefore, we hypothesized that HTG promotes TNBC growth and progression by increased VLDL uptake through the VLDLR, which contributes to lipid peroxidation in hypoxic tumors. We hypothesize that lipid peroxidation increases cell signaling which enhances tumor survival in the setting of hypoxia, and also contributes to EMT, cytoskeletal changes and changes in the tumor immune microenvironment. In this project we will explore the importance of tumor VLDLR expression in HTG-driven TNBC growth and metastasis using patient derived xenografts. Secondly, we will examine the importance of an abundant lipid peroxidation product in TNBC. Finally, we will explore therapeutic strategies to lower TG, which if successful could readily be translated into clinical care to improve outcomes for women with HTG and TNBC.