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 the development of precision dietary intervention strategies. In this study, we used murine models of obesity induced by different high-fat diets (HFD) to examine their impact on TNBC progression. Compared with a low-fat diet, both cocoa butter and olive oil HFDs 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 the consumption of olive oil HFD promotes obesity-associated TNBC metastasis through OA/FABP5-driven oncogenic signaling. SIGNIFICANCE: Comparison of obesity induced by different high-fat diets revealed that an olive oil-based diet promotes triple-negative breast cancer metastasis by activating FABP5/PKC/ALDH signaling, providing a target for the development of obesity-associated cancer therapeutics.