Dietary lipids as drivers and therapeutic targets in obesity-accelerated breast cancer

Summary Diet-induced obesity affects about 40 percent of US women and increases the incidence, morbidity, and mortality of postmenopausal breast cancer (BC). Obesity also increases the risk of large, high-grade tumors, metastasis, and recurrence regardless of menopausal status. Our long-term goal is to contribute to the development of new therapeutic approaches for the treatment of obesity-associated human BC. Our research proposal addresses this by interrogating the mechanisms by which dietary lipids accelerate BC tumor growth, and whether BC in patients with obesity have unique metabolic vulnerabilities that can be leveraged therapeutically. Supported by published evidence and our own preliminary data, our central hypothesis is that, in settings of chronic dietary lipid overabundance such as obesity, BC cells are wired to utilize free fatty acids (FFA) over glucose to support cancer lipid anabolism, resulting in accelerated tumor growth. The insulin sensitivity and health of the adipose microenvironment dictate whether tumors source these lipids locally or from systemic metabolism. We will test our central hypothesis by pursuing three specific aims: 1) Test if dietary lipids, rather than glucose, are preferentially utilized by BC cells in lipid-rich environments, 2) Determine the metabolic fate of absorbed fatty acids in breast tumors and 3) Assess the translational implications of an altered metabolic program to the treatment of BC in patients with obesity. In aim 1, we will use different dietary and genetic mouse models that can accelerate BC growth to quantify the relative uptake of dietary fuels and their source in lean versus obese BC. In aim 2, we will use stable isotope infusions to trace the fates of dietary- derived FFAs and establish their biochemical contributions to tumor growth. In aim 3, we will use pharmacological inhibitors of lipolysis and circulating FFA-lowering agents to test the therapeutic potential of restricting FFA supply for inhibiting tumor growth. We will also analyze the expression of lipid metabolism genes in human BC stratified by body mass index as a measure of obesity status. Our approach, which collectively addresses physiology, adipose biology, and tumor metabolism, is enabled by our combined expertise in nutrition and metabolic status (Dr. Chaix), adipose tissue biology (Dr. Hilgendorf), and in vivo stable isotope tracing to study tumor metabolism (Dr. Ducker). Together, we have established a system in which BC tumor growth can be accelerated solely by the manipulation of circulating levels of lipids, independent of adiposity and associated metabolic syndrome. This lipid-centric view of tumor metabolism generates strong testable hypotheses for future therapeutic interventions. Specifically, we propose that pharmacological and dietary interventions targeting cancer metabolism need to be optimized for the lipid metabolic program of the tumors which is determined by the metabolic health of the patient.