An Olive Oil-Based High-Fat Diet Promotes Obesity-Driven Metastasis of Triple-Negative Breast Cancer

Obesity is strongly associated with triple-negative breast cancer (TNBC). A better understanding of the molecular mechanisms driving obesity-induced TNBC progression could facilitate development of precision dietary intervention strategies. Here, we used murine models of obesity induced by different high-fat diets (HFDs) to examine their impact on TNBC progression. Compared to a low-fat diet (LFD), both cocoa butter and olive oil HFD induced similar levels of obesity. However, only the olive oil HFD-induced obesity increased TNBC stemness and lung metastasis. Mechanistically, oleic acid (OA) in the olive oil HFD facilitated TNBC metastasis by activating the protein kinase C (PKC)-aldehyde dehydrogenase (ALDH) pathway. Furthermore, fatty acid-binding protein 5 (FABP5) in TNBC cells was identified as essential for OA-mediated PKC/ALDH pathway activation. FABP5 deficiency reduced TNBC metastasis in multiple mouse models, whereas higher FABP5 expression correlated with worse outcomes of TNBC in various human studies. These findings collectively suggest that consumption of olive oil HFD promotes obesity-associated TNBC metastasis through OA/FABP5-driven oncogenic signaling.