Triple-Negative breast cancer metastasis promoted by PKCeta/Yap/Taz signaling axis, presenting a new target for therapy

Protein kinase C (PKC) enzymes are essential serine/threonine kinases playing a role in cellular functions, including cell proliferation, survival, and apoptosis. Protein kinase C eta (PKCη), an anti-apoptotic kinase member of the novel PKCs subfamily, is associated with poor prognosis in breast cancer patients. Here we demonstrate that PKCη promotes metastasis in triple-negative breast cancer (TNBC) cells and show that this is mediated by PKCƞ-YAP signaling axis. Using PKCƞ knockout (CRISPR/Cas9) of 4T1 and MDA-MB-231 cells, we show that ablation of PKCη expression (PKCηKO) reduces cell proliferation, colony formation, and in vitro tumorigenicity of these triple-negative breast cancer cells. Moreover, PKCηKO significantly reduced cell migration and invasion, as demonstrated by wound healing and Boyden chamber assays. Orthotropic mammary xenografts of NSG mice with PKCηKO 4T1 and MDA-MB-231 cells exhibited reduced tumor growth and organ metastasis. Depleting PKCη in 4T1 and MDA-MB-231 resulted in decreased epithelial-mesenchymal transition (EMT) characteristics as indicated by the altered expression of EMT markers, including E-cadherin, slug, snail, and ZEB. Furthermore, our data showed that knockout of PKCη significantly reduced nuclear YAP and YAP/TAZ phosphorylation levels, indicating that PKCη acts as a regulator of the Hippo-YAP pathway. Taken together, our study demonstrates that PKCη promotes triple-negative breast cancer metastasis by modulating the YAP/Hippo pathway. Thus, PKCη can be considered a potential target for therapy in breast cancer metastasis.