title: The calcium pump plasma membrane Ca(2+)-ATPase 2 (PMCA2) regulates breast cancer cell proliferation and sensitivity to doxorubicin.
abstract: 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.
authors.affiliation: School of Pharmacy, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Amelia A
authors.initials: AA
authors.lastname: Peters
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Michael J G
authors.initials: MJ
authors.lastname: Milevskiy
authors.affiliation: School of Pharmacy, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Wei C
authors.initials: WC
authors.lastname: Lee
authors.affiliation: School of Pharmacy, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Merril C
authors.initials: MC
authors.lastname: Curry
authors.affiliation: UQ Centre for Clinical Research, The University of Queensland, Herston, Queensland, 4006, Australia.|School of Medicine, University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Chanel E
authors.initials: CE
authors.lastname: Smart
authors.affiliation: UQ Centre for Clinical Research, The University of Queensland, Herston, Queensland, 4006, Australia.|QIMR Berghofer Medical Research Institute, Cancer Genetics, Herston, Queensland, 4006, Australia.
authors.forename: Jodi M
authors.initials: JM
authors.lastname: Saunus
authors.affiliation: UQ Centre for Clinical Research, The University of Queensland, Herston, Queensland, 4006, Australia.|QIMR Berghofer Medical Research Institute, Cancer Genetics, Herston, Queensland, 4006, Australia.
authors.forename: Lynne
authors.initials: L
authors.lastname: Reid
authors.affiliation: UQ Centre for Clinical Research, The University of Queensland, Herston, Queensland, 4006, Australia.|QIMR Berghofer Medical Research Institute, Cancer Genetics, Herston, Queensland, 4006, Australia.
authors.forename: Leonard
authors.initials: L
authors.lastname: da Silva
authors.affiliation: School of Pharmacy, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Daneth L
authors.initials: DL
authors.lastname: Marcial
authors.affiliation: School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, 4102, Australia.
authors.forename: Eloise
authors.initials: E
authors.lastname: Dray
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: UQ Centre for Clinical Research, The University of Queensland, Herston, Queensland, 4006, Australia.|School of Medicine, University of Queensland, Brisbane, Queensland, 4072, Australia.|Pathology Queensland, The Royal Brisbane &Women's Hospital, Brisbane, Queensland, 4006, Australia.
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Lakhani
authors.affiliation: School of Pharmacy, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Roberts-Thomson
authors.affiliation: School of Pharmacy, The University of Queensland, Brisbane, Queensland, 4072, Australia.|Mater Research Institute, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Monteith
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002280:Basal Cell Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000494:pharmacology; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007774:Lactation / Q000502:physiology; D042361:Mammary Glands, Human / Q000201:enzymology / Q000473:pathology; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D000903:Antibiotics, Antineoplastic; D007527:Isoenzymes; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004317:Doxorubicin; D053499:Plasma Membrane Calcium-Transporting ATPases; D002118:Calcium