Calcium sensing receptor stimulates breast cancer cell migration and invasion via protein kinase C ζ

Calcium-sensing receptor (CaSR), a G protein-coupled receptor, is overexpressed in certain breast cancer tumors where it drives cell migration and secretion of chemotactic agonists, likely contributing to metastatic dissemination. Since CaSR activates breast cancer cell migration via the Gβγ-PI3K-mTORC2/Rac-1 pathway, we hypothesized that PKCζ and perhaps other protein kinase C (PKC) isoforms, known as mTORC2-regulated effectors, are involved in migratory and invasive signaling elicited by CaSR. We analyzed the effect of PKC inhibitors and siRNAs which pointed to PKCζ as effector of CaSR in cell migration and invasion. In breast cancer phosphoproteomic CPTAC datasets, we identified a group of Luminal A subtype cancer patients having active PKCζ, according to its phosphorylation status at the turn motif. In addition, various phosphorylated RacGEFs, including TRIO, ARHGEF26, DOCK1 and DOCK7, clustered as phosphoproteins with active PKCζ. We therefore introduce atypical PKCζ as an effector component of the CaSR-Gβγ-PI3K-mTORC2 pathway in the activation of the promigratory small GTPase Rac. These results support ongoing initiatives to establish critical elements of the CaSR signaling pathway as potential targets in metastatic breast cancer.