The calcium pump plasma membrane Ca2+-ATPase 2 (PMCA2) regulates breast cancer cell proliferation and sensitivity to doxorubicin

Amelia A. Peters, Michael J. G. Milevskiy, Wei C. Lee, Merril C. Curry, Chanel E. Smart, Jodi M. Saunus, Lynne Reid, Leonard da Silva, Daneth L. Marcial, Eloise Dray, Melissa A. Brown, Sunil R. Lakhani, Sarah J. Roberts-Thomson, Gregory R. Monteith

Regulation of Ca(2+) transport is vital in physiological processes, including lactation, proliferation and apoptosis. The plasmalemmal Ca(2+) pump isoform 2 (PMCA2) a calcium ion efflux pump, was the first protein identified to be crucial in the transport of Ca(2+) ions into milk during lactation in mice. In these studies we show that PMCA2 is also expressed in human epithelia undergoing lactational remodeling and also report strong PMCA2 staining on apical membranes of luminal epithelia in approximately 9% of human breast cancers we assessed. Membrane protein expression was not significantly associated with grade or hormone receptor status. However, PMCA2 mRNA levels were enriched in Basal breast cancers where it was positively correlated with survival. Silencing of PMCA2 reduced MDA-MB-231 breast cancer cell proliferation, whereas silencing of the related isoforms PMCA1 and PMCA4 had no effect. PMCA2 silencing also sensitized MDA-MB-231 cells to the cytotoxic agent doxorubicin. Targeting PMCA2 alone or in combination with cytotoxic therapy may be worthy of investigation as a therapeutic strategy in breast cancer. PMCA2 mRNA levels are also a potential tool in identifying poor responders to therapy in women with Basal breast cancer.