Investigating the role of Wnt/planar cell polarity signaling in the reprogramming of energy metabolism in breast cancer

This study aims to investigate how non-canonical Wnt/planar cell polarity (Wnt/PCP) signaling contributes to metabolic reprogramming and supports breast cancer progression. Breast cancer is the most prevalent cancer affecting women, and the 5-year survival rate for women diagnosed with metastatic breast cancer remains below 30%. For breast tumors to progress and ultimately result in metastatic disease, large increases in energy demands must be met. Tumors gain bioenergetic versatility by undergoing metabolic reprogramming through the upregulation of glycolytic and oxidative phosphorylation (OXPHOS) activity, and through alterations in mitochondrial biogenesis and degradation (mitophagy). However, the signal transduction pathways critical to sustaining the high levels of ATP production remain largely undefined. The non-canonical Wnt/PCP signaling pathway has been implicated in promoting tumor cell migration and metastasis in diverse tumor types. Our laboratory has reported that the Wnt/PCP-specific transmembrane protein Vangl mediates breast cancer collective migration and metastasis. Further, our recent proteomics and metabolomics studies indicate that Vangl1 regulates the expression of critical components in the OXPHOS pathway in vivo and in vitro, and that the Wnt/PCP ligand Wnt5a alters the phosphorylation of proteins involved in mitochondrial biogenesis and mitophagy. Thus, I propose that Wnt/PCP signaling regulates the reprogramming of energy metabolism to drive cell proliferation and motility in breast cancer. This will be tested by investigating the contribution of Wnt/PCP signaling to OXPHOS activity and the regulation of mitochondrial biogenesis and mitophagy in breast cancer. This study will promote our understanding of Wnt/PCP involvement in breast cancer progression and provide new insights into the mechanisms contributing to cancer metabolic reprogramming.