PKC-eta promotes breast cancer metastasis by regulating the Hippo-YAP signaling pathway

Triple-negative breast cancer (TNBC) is an aggressive disease characterized by high metastatic potential and limited treatment options. Protein kinase C-eta (PKCη), an antiapoptotic kinase of the novel PKC subfamily, is associated with poor prognosis in breast cancer patients. Analysis of TNBC tumors revealed that PRKCH (PKCη) expression is linked to an epithelial‒mesenchymal transition (EMT) signature, which is indicative of a metastatic phenotype. Using genetic ablation studies, we showed that PKCη promotes metastasis by enhancing EMT and stemness. Notably, compared with those in PKCη-intact tumors, orthotopic xenografts of PKCη-knockout cells in NSG mice resulted in reduced tumor growth and metastasis. Mechanistically, PKCη functions as a negative regulator of the Hippo pathway by activating YAP. PKCη phosphorylates YAP at Ser128, leading to its stabilization and nuclear translocation, which promotes metastasis. We also demonstrated that PKCη negatively regulates AKT, thereby further sustaining the downregulation of the Hippo pathway. Finally, we show that an evolutionarily conserved peptide encoded by an upstream open reading frame (uORF) preceding the PKCη coding sequence functions as a PKCη degrader, activating the Hippo pathway and promoting YAP degradation. Together, our findings reveal a PKCη-driven signaling axis that regulates the Hippo-YAP pathway in TNBC metastasis, highlighting the potential therapeutic vulnerability of this aggressive disease.