The calcium pump PMCA4b promotes epithelial cell polarization and lumen formation

• Published in: Communications biology Vol. 8; no. 1; pp. 421 - 18
• Main Authors: Tóth, Sarolta, Kaszás, Diána, Sónyák, János, Tőkés, Anna-Mária, Padányi, Rita, Papp, Béla, Nagy, Réka, Vörös, Kinga, Csizmadia, Tamás, Tordai, Attila, Enyedi, Ágnes
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.03.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/109; 13/51; 13/95; 14; 14/19; 14/28; 14/34; 14/35; 14/63; 38; 38/89; 631/67/1347; 631/80/85/2361; 64; 64/24; 82/29; 82/51; Animals; Biomedical and Life Sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Ca2+-transporting ATPase; Calcium signalling; Carcinogenesis; Cell Polarity; Down-regulation; Drosophila melanogaster - genetics; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Epithelial cells; Epithelial Cells - metabolism; Female; Humans; Life Sciences; MCF-7 Cells; Morphogenesis; Plasma Membrane Calcium-Transporting ATPases - genetics; Plasma Membrane Calcium-Transporting ATPases - metabolism; Polarity; Polarization; Salivary gland
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-025-07814-5

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. We identify Arf6 as a regulator of PMCA4b endocytic recycling essential for PMCA4-mediated 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 role of PMCA4 in controlling epithelial cell polarity, and in the maintenance of normal glandular tissue architecture. PMCA4 promotes epithelial polarization and lumen formation, while its loss induces partial EMT in luminal breast cancer cells. Its downregulation in LUMA/B1 breast cancer correlates with poor survival and may therefore serve as a prognostic marker.