YAP Dictates Mitochondrial Redox Homeostasis to Facilitate Obesity-Associated Breast Cancer Progression.

Abstract

Dysregulation of hormones is considered a risk factor for obesity‐mediated breast tumorigenesis; however, obesity is associated with poor outcomes among women diagnosed with triple‐negative breast cancer (TNBC), which is a hormone‐independent breast cancer subtype. Thus, identifying the driving force behind the obesity‐breast cancer relationship is an urgent need. Here it is identified that diet‐induced obesity (DIO) facilitates tumorigenesis of TNBC cells. Mechanistically, DIO induces a metabolic addiction to fatty acid oxidation (FAO), accompanied by coordinated activation of Yes‐associated protein (YAP) signaling. Specifically, YAP governs mitochondrial redox homeostasis via transcriptional regulation of antioxidant‐related enzymes, which renders tumor cells capable of extenuating FAO‐elicited mitochondrial oxidative stress. Moreover, adipocytes‐derived fatty acids are identified to be responsible for enhancing the FAO‐YAP axis and antioxidative capacity, and higher expression of an obesity signature in breast cancer patients is positively correlated with YAP signaling and antioxidant genes. The findings uncover the crucial role of YAP in dictating mitochondrial redox homeostasis for obesity‐mediated metabolic adaptation and breast tumor progression.