title: ORAI1-mediated calcium influx in lactation and in breast cancer.
abstract: The entry of calcium into the mammary epithelial cell from the maternal plasma (i.e., calcium influx mechanisms) during lactation is poorly understood. As alterations in calcium channels and pumps are a key feature of some cancers, including breast cancer, understanding these calcium influx pathways may have significance beyond mammary biology. We show that the store-operated calcium influx protein, Orai1, is increased during lactation whereas the Orai1 activator Stim1, but not Stim2, is downregulated. Stim2 siRNA reduced basal calcium levels in a lactation model. Our results suggest that calcium influx is remodeled in mammary epithelial cells during lactation, with calcium influx increased through Orai1, activated by Stim2. Breast cancer cell lines had increased levels of ORAI1. ORAI1 siRNA in breast cancer cells reduced store-operated calcium entry and remodeled the calcium influx associated with invasive stimuli. Analysis of microarray data from 295 breast cancers showed that the transcriptional breast cancer subtype with the poorest prognosis (basal) was associated with an altered relationship between the ORAI1 regulators STIM1 and STIM2, and that women with breast cancers with STIM1(high)/STIM2(low) tumors had a significantly poorer prognosis. Our studies show that during lactation there is a remodeling in the nature of calcium influx and that alteration in the ORAI1 influx pathway may be a feature of some breast cancers, particularly those with the poorest prognosis. Our studies suggest that this pathway may be a novel therapeutic target for breast cancer treatment in these women.
authors.affiliation: School of Pharmacy, The University of Queensland, Brisbane, Queensland Australia, 4072.
authors.forename: Damara
authors.initials: D
authors.lastname: McAndrew
authors.forename: Desma M
authors.initials: DM
authors.lastname: Grice
authors.forename: Amelia A
authors.initials: AA
authors.lastname: Peters
authors.forename: Felicity M
authors.initials: FM
authors.lastname: Davis
authors.forename: Teneale
authors.initials: T
authors.lastname: Stewart
authors.forename: Michelle
authors.initials: M
authors.lastname: Rice
authors.forename: Chanel E
authors.initials: CE
authors.lastname: Smart
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Brown
authors.forename: Paraic A
authors.initials: PA
authors.lastname: Kenny
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Roberts-Thomson
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Monteith
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007774:Lactation / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000071740:ORAI1 Protein; D034741:RNA, Small Interfering; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2
chemical_list: D015220:Calcium Channels; D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C520430:Orai1 protein, mouse; D034741:RNA, Small Interfering; C103530:STIM1 protein, human; C513279:STIM2 protein, human; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D002118:Calcium