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

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

doi:10.1038/srep25505

Abstract

Regulation of Ca2+ transport is vital in physiological processes, including lactation, proliferation and apoptosis. The plasmalemmal Ca2+ pump isoform 2 (PMCA2) a calcium ion efflux pump, was the first protein identified to be crucial in the transport of Ca2+ 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.

Highlights

The enrichment of milk with calcium is vital to neonatal and infant development
PMCA2 mRNA levels are elevated in some breast cancer cell lines[20], and a tissue microarray (TMA) study suggested that high expression of PMCA2 protein predicts poor survival in patients under 50 years of age, and is associated with HER2-positive disease[19]
Elevated PMCA2 is a feature of mammary glands from lactating mice[2,22], PMCA2 expression has not been assessed in human breast tissue undergoing lactational change

Summary

Introduction

The enrichment of milk with calcium is vital to neonatal and infant development. The process by which calcium ions are transferred from the maternal blood supply into milk is highly coordinated, and involves specific calcium-permeable ion channels, and calcium pumps of both the secretory pathway and plasma membrane[1,2,3,4,5,6]. Recent studies have associated many of these specific calcium channels and pumps in processes important in breast cancer progression. Specific calcium channels and pumps are identified as potential therapeutic targets in a number of cancer types including those of the prostate and breast[8,9]. The secretory pathway Ca2+-ATPase isoform 2 (SPCA2) is associated with increased expression during lactation and specific breast cancer subtypes[2,13]. PMCA2 mRNA levels are elevated in some breast cancer cell lines[20], and a tissue microarray (TMA) study suggested that high expression of PMCA2 protein predicts poor survival in patients under 50 years of age, and is associated with HER2-positive disease[19]. The biological role of PMCA2 in breast carcinogenesis is generally not well understood, and the breast cancer subtypes where it might be most important and its potential utility as a therapeutic target are still unclear

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Conclusion