Identification of Putative Fatty Acid Binding Protein 4 Receptors on Breast Cancer Epithelial Cells

Abstract

Fatty acid binding protein 4 (FABP4) is a small 15-kDa cytoplasmic lipid carrier protein regulating fatty acid trafficking and metabolism. It is one of the most abundant proteins in mature adipocytes and can be secreted into the extracellular environment upon lipolytic stimulus, functioning as an adipokine. Elevated circulating FABP4 levels have been associated with obesity-related and inflammation-related diseases. Recent studies have indicated FABPP4 as a potential biomarker in cancer diagnosis and prognosis. FABP4 upregulation or exogenous FABP4 (eFABP4) administration has been found to promote cancer growth, invasion and metastasis, while FABP4 inhibition reduced cancer progression. Understanding the molecular mechanism underlying FABP4 effects in cancer is critical for developing anticancer drugs. Although exogenous FABP4 has been found to exert pro-tumorigenic effects, there is no known FABP4 receptor that transduces its signaling into intracellular responses. Identifying a FABP4 receptor would be significant for targeting FABP4 in cancers. Furthermore, although fatty acids have been found to be essential in FABP4 function, the mechanisms explaining their collaboration remain largely unknown. This thesis aims to identify putative FABP4 receptors on cancer cell plasma membrane to understand FABP4 signaling in breast cancer cells. Our work reveals that eFABP4 binds to the extracellular domain of desmoglein 2 to mediate breast cancer epithelial cell growth via an ERK-NRF2 axis, suggesting desmoglein 2 as a FABP4 receptor. We also find that fatty acids enhance the interaction between FABP4 and desmoglein 2, which may explain why non-fatty acid binding mutants of FABP4 abolish FABP4 effects and support the role of fatty acids in FABP4 signaling. In conclusion, our findings provide new insights into the mechanism of FABP4 in the development and progression of obesity-associated cancers.