Abstract Loss of epithelial cell polarity and tissue disorganization are hallmarks of carcinogenesis, in which Ca 2+ signaling plays a significant role. Here we demonstrate that the plasma membrane Ca 2+ pump PMCA4 (ATP2B4) is downregulated in luminal breast cancer, and this is associated with shorter relapse-free survival in patients with luminal A and B1 subtype tumors. Using the MCF-7 breast cancer cell model we show that PMCA4 silencing results in the loss of cell polarity while a forced increase in PMCA4b expression induces cell polarization and promotes lumen formation in 2D and 3D cell cultures. We identify Arf6 as a novel regulator of PMCA4b endocytic recycling essential for PMCA4 regulated lumen formation. Silencing of the single pmca gene in Drosophila melanogaster larval salivary gland destroys lumen morphology suggesting a conserved role of PMCAs in lumen morphogenesis. Our findings point to a novel role of PMCA4 in controlling epithelial cell polarity, and in the maintenance of normal glandular tissue architecture.

The calcium pump PMCA4b promotes epithelial cell polarization and lumen formation