Abstract P263: Interaction between CD36 and FABP4 regulates the import and metabolism of fatty acid in breast cancer cells

Abstract

Abstract The breast cancer microenvironment is unique since the breast tissue within which the tumour originates comprises predominantly adipocytes. Adipocytes secrete various growth factors and cytokines that are reported to influence tumour progression by induction of epithelial-mesenchymal transition (EMT) which enhances cancer cell migration, invasion, and metastasis. Immunohistochemical analysis reveals that the invading breast cancer invades surrounding adipose tissues resulting in the delipidation of adipose tissues. To determine the molecular mechanism underlying these events, we co-cultured human adipocytes and breast cancer cells. Co-cultured cells had increased CD36 expression, with fatty acid import. Genetic ablation of CD36 attenuates adipocyte-induced EMT and stemness. Molecular screening for pathways potentially involved in adipocyte-induced CD36 expression reveals activation of the STAT3 signaling axis. Our study identifies a feedforward loop between CD36 and STAT3; where STAT3 binds to the CD36 promoter, activating its expression and CD36 upregulates STAT3 signaling. Breast cancer cells co-cultured with adipocytes actively accumulate fatty acids and undergo metabolic reprogramming, with a shift towards fatty acid oxidation. Seahorse metabolic analysis reveals that co-cultured CD36-expressing cells assumed an energetic phenotype, indicating enhanced mitochondrial respiration. Thus, breast cancer cells alter their metabolic programs, with increased mitochondrial respiration, to meet their energy needs, with the availability of fatty acids. Analysis of breast cancer patient data reveals that increased CD36 expression occurs with increased FABP4 expression. Mechanistic experiments reveal that CD36 directly interacts with FABP4 to regulate fatty acid import, transport, and metabolism in co-cultured breast cancer cells. In vivo studies in mouse models reveal that combined chemical inhibition of CD36 and FABP4 resulted in a significant reduction in tumour growth rate. The study presents an alternative approach by which adipocytes may enhance cancer progression via the transfer of free fatty acids from tumour-associated adipocytes to breast cancer cells. The uptake of free fatty acid subsequently serves as a secondary source of energy to drive breast cancer cell progression. Targeting CD36 in combination with FABP4 may have a potential for therapies targeting the breast cancer microenvironment. Citation Format: Jones Gyamfi, Junjeong Choi, Doru Kwon, JaSeung Koo. Interaction between CD36 and FABP4 regulates the import and metabolism of fatty acid in breast cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P263.