CCN6 (cellular communication network factor 6) is a matricellular protein with dual functions as both a secreted signaling molecule and an intracellular regulator of mitochondrial function. As a secreted protein, CCN6 acts as a tumor suppressor in breast cancer by antagonizing Wnt/β-catenin signaling through interaction with FZD8 and LRP6 receptors, thereby preventing epithelial-to-mesenchymal transition and inhibiting EZH2-driven metastasis 1. CCN6 expression is reduced in aggressive breast cancer phenotypes, particularly metaplastic carcinomas, where it normally maintains epithelial phenotype and inhibits tumor progression 2. Intracellularly, CCN6 localizes to mitochondria and regulates electron transport chain activity, mitochondrial respiration, and ATP synthesis 3. It also functions in transcriptional regulation by associating with RNA Polymerase II and controlling expression of mitochondrial electron transport complex genes 4. CCN6 protein levels are regulated by the ubiquitin-proteasome system, with OTUB1 acting as a deubiquitinating enzyme that stabilizes CCN6 through non-canonical mechanisms 5. Mutations in CCN6 cause Progressive Pseudorheumatoid Dysplasia, likely through impaired mitochondrial function affecting cartilage and muscle homeostasis 4.