A Mount Sinai researcher in 2022 received a $2.5 million, five-year grant from the National Institutes of Health (NIH) to conduct a novel study into the mechanisms linking elevated triglyceride levels and triple negative breast cancer.

Emily Gallagher, MD, PhD, Associate Professor of Medicine (Endocrinology, Diabetes and Bone Disease) at the Icahn School of Medicine at Mount Sinai, received the Method to Extend Research in Time (MERIT) Award from the National Cancer Institute (NCI), part of the NIH, to study the role of high triglyceride levels in driving triple negative breast cancer growth and metastasis. Dr. Gallagher is a physician-scientist with a clinical practice in the field of onco-endocrinology, the management of endocrine and metabolic complications of cancer.

More than 50 percent of women with triple negative breast cancer have elevated circulating triglycerides and these elevated levels are associated with reduced breast cancer survival. Further, a number of factors, including obesity, diabetes, high carbohydrate diets, and excess alcohol consumption can contribute to high circulating triglyceride levels. The link between hypertriglyceridemia (HTG) and triple negative breast cancer has been described in epidemiology studies, but checking and treating triglyceride levels in women with triple negative breast cancers is not part of standard oncology care.

“This grant from the NIH/NCI will give us a better understanding of how elevated triglycerides contribute to triple negative breast cancer growth and metastasis—something that, mechanistically, hasn’t been previously studied,” says Dr. Gallagher, who is also Director of the Research Pathway, and Associate Program Director of the Internal Medicine Residency Program, both at Icahn Mount Sinai.

The grant will allow Dr. Gallagher and her team to explore how human breast cancers take up triglycerides from circulation in the form of very-low-density lipoproteins. To understand the biological links between HTG and the progression of triple negative breast cancer, the team is employing preclinical models of hypertriglyceridemia in isolation from other metabolic abnormalities. In preliminary studies, the team found that the mice with HTG develop more rapid growth and metastasis of triple negative breast cancers.

The HTG mice demonstrated lipid profiles with elevated very-low-density lipoprotein (VLDL) and high circulating of phospholipids associated with elevated VLDL. The team hypothesized that HTG promotes the growth and progression of triple negative breast cancer by increased VLDL uptake through the VLDL receptor, which contributes to lipid peroxidation products in hypoxic tumors. They hypothesized that lipid peroxidation affects cell signaling pathways, which enhance tumor cell survival and metastasis.

The team is also exploring the importance of tumor VLDL receptor expression in HTG-driven cancer growth and metastasis using xenografts derived from human triple negative breast cancers. Additionally, the researchers will examine therapeutic strategies to lower triglycerides, which, if successful, could be translated into clinical care to improve outcomes for women with high triglyceride levels and triple-negative breast cancer.

“In my oncoendocrinology clinical practice, I see many women who have high triglycerides and breast cancer, sometimes as a result of their breast cancer treatment,” Dr. Gallagher says. “My hope is that through this funding, we will be able to determine in preclinical models if starving triple negative cancer cells of these lipids can be exploited as a novel therapeutic strategy. Ultimately, my goal is to improve outcomes for women living with triple negative breast cancer and metabolic conditions."