Oncogenic signaling of the free-fatty acid receptors FFA1 and FFA4 in human breast carcinoma cells

Globally, breast cancer is the most frequent type of cancer in women, and most breast cancer-associated deaths are due to metastasis and recurrence of the disease. Dietary habits, specifically dietary fat intake is a crucial risk factor involved in breast cancer development and progression. Decades of research has revealed that free-fatty acids (FFA) modulate carcinogenic processes through fatty acid metabolism and lipid peroxidation. The ground-breaking discovery of free-fatty acid receptors, which are members of the G-protein coupled receptor (GPCR) superfamily, has led to the realization that FFA can also act via these receptors to modulate carcinogenic effects. The long-chain free-fatty acid receptors FFA1 (previously termed GPR40) and FFA4 (previously termed GPR120) are activated by mono- and polyunsaturated fatty acids including ω-3, 6, and 9 fatty acids. Initial enthusiasm towards the study of these receptors focused on their insulin secretagogue and sensitization effects, and the downstream associated metabolic regulation. However, recent studies have demonstrated that abnormal expression and/or aberrant FFA1/FFA4 signaling are evident in human breast carcinomas, suggesting that FFA receptors could be a promising target in the treatment of breast cancer. The current review discusses the diverse roles of FFA1 and FFA4 in the regulation of cell proliferation, migration, invasion, and chemotherapy resistance in human breast carcinoma cells and tissue.