Determining the role of FABP5 in linking high FAT diet-induced obesity to triple negative breast cancer progression - the objective of this proposal is to elucidate the molecular and metabolic…

The National Cancer Institute awarded a $644,398 cooperative agreement to the University of Iowa on September 1, 2026, under the Cancer Biology Research program (CFDA 93.396) to investigate the molecular and metabolic mechanisms linking high-fat diet-induced obesity to triple negative breast cancer progression.

The research focuses on the role of FABP5, a lipid chaperone protein, in connecting obesity-associated lipid dysregulation to triple negative breast cancer metastasis. The project consists of three aims: determining which types of high-fat diets drive obesity-associated triple negative breast cancer through a FABP5-dependent mechanism; delineating the molecular mechanisms by which FABP5 promotes obesity-driven triple negative breast cancer progression through three fundamental lipid functions (energy production, membrane incorporation, and oncogenic signaling); and identifying FABP5 as both a biomarker and therapeutic target for obesity-associated triple negative breast cancer progression. Preliminary studies demonstrated that while different high-fat diets can induce obesity, only olive oil-based monounsaturated fats increased triple negative breast cancer metastasis in mouse models and that FABP5 promotes dietary oleic acid-induced triple negative breast cancer migration.

Performance occurs in Iowa City, Iowa, with a project period from September 1, 2026, through August 31, 2031.

Determining the role of FABP5 in linking high FAT diet-induced obesity to triple negative breast cancer progression - the objective of this proposal is to elucidate the molecular and metabolic mechanisms by which the lipid chaperone FABP5 (epithelial fatty acid binding protein, also known as e-fabp) links high FAT diet (HFD)-induced obesity to triple negative breast cancer (tnbc) progression. Obesity-associated lipid dysregulation has been implicated in increased breast cancer risk and progression, including tnbc. In preliminary studies, we demonstrated that while obesity can be induced by different types of hfds, including saturated fats (e.g., cocoa butter), monounsaturated fats (e.g., olive oil), or polyunsaturated fats (e.g., safflower oil), not all HFD-induced obesity promotes tnbc progression. Specifically, olive oil-based monounsaturated fats, but not saturated or polyunsaturated fats, increased tnbc metastasis in mouse models. Furthermore, we found that FABP5 promotes dietary oleic acid-induced tnbc migration, suggesting that FABP5 is a critical link between obesityassociated lipid dysregulation and tnbc metastasis. Given the undefined mechanisms underlying obesity-driven tnbc progression, we hypothesize that hfds rich in monounsaturated fats promote tnbc metastasis through FABP5-mediated lipid metabolic dysregulation. Thus, FABP5 represents both a biomarker and a therapeutic target for obesity-associated tnbc progression. To test this hypothesis, we propose three complementary yet independent aims: aim 1 is to determine the role of FABP5 in linking different types of HFD-induced obesity to tnbc progression. We will identify which specific hfds drive obesity-associated tnbc via a FABP5-dependent mechanism. Aim 2 is to delineate the molecular mechanisms by which FABP5 promotes obesity-driven tnbc progression. We will determine how FABP5 drives tnbc progression through three fundamental lipid functions: energy production, membrane incorporation and oncogenic signaling. Aim 3 is to evaluate FABP5 as a biomarker and therapeutic target for obesity-associated tnbc using clinical specimens and proprietary anti-FABP5 monoclonal antibodies. Animal studies are essential because diet-induced obesity, systemic lipid metabolism, the tumor microenvironment, and metastatic progression cannot be adequately modeled in vitro or in silico. FABP5 knockout mice enable direct determination of the causal role of FABP5 in HFD-induced tnbc progression, and findings from these studies will be validated using human clinical specimens. Successful completion of this proposal will establish FABP5 as a key mediator of HFD-induced tnbc progression by driving lipid metabolism and oncogenic signaling. These findings will position FABP5 as a novel biomarker and therapeutic target for lipid-driven tnbc progression.