title: A role for calcium in the regulation of ATP-binding cassette, sub-family C, member 3 (ABCC3) gene expression in a model of epidermal growth factor-mediated breast cancer epithelial-mesenchymal transition.
abstract: Epithelial-mesenchymal transition (EMT), a process implicated in cancer metastasis, is associated with the transcriptional regulation of members of the ATP-binding cassette superfamily of efflux pumps, and drug resistance in breast cancer cells. Epidermal growth factor (EGF)-induced EMT in MDA-MB-468 breast cancer cells is calcium signal dependent. In this study induction of EMT was shown to result in the transcriptional up-regulation of ATP-binding cassette, subfamily C, member 3 (ABCC3), a member of the ABC transporter superfamily, which has a recognized role in multidrug resistance. Buffering of cytosolic free calcium inhibited EGF-mediated ABCC3 increases, indicating a calcium-dependent mode of regulation. Silencing of TRPM7 (an ion channel involved in EMT associated vimentin induction) did not inhibit ABCC3 up-regulation. Silencing of the store operated calcium entry (SOCE) pathway components ORAI1 and STIM1 also did not alter ABCC3 induction by EGF. However, the calcium permeable ion channel transient receptor potential cation channel, subfamily C, member 1 (TRPC1) appears to contribute to the regulation of both basal and EGF-induced ABCC3 mRNA. Improved understanding of the relationship between calcium signaling, EMT and the regulation of genes important in therapeutic resistance may help identify novel therapeutic targets for breast cancer.
authors: School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia. Electronic address: teneale.stewart@uq.edu.au.
authors: Teneale A
authors: TA
authors: Stewart
authors: School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia. Electronic address: i.azimi@uq.edu.au.
authors: Iman
authors: I
authors: Azimi
authors: Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, Queensland, Australia; University of Melbourne Department of Surgery, St. Vincent's Hospital, Melbourne, Australia. Electronic address: e2.thompson@qut.edu.au.
authors: Erik W
authors: EW
authors: Thompson
authors: School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia. Electronic address: sarahrt@uq.edu.au.
authors: Sarah J
authors: SJ
authors: Roberts-Thomson
authors: School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia. Electronic address: gregm@uq.edu.au.
authors: Gregory R
authors: GR
authors: Monteith
mesh_terms: D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D050052:TRPC Cation Channels / Q000378:metabolism
chemical_list: D002118:Calcium; D004815:Epidermal Growth Factor; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; C114462:multidrug resistance-associated protein 3
keywords: ABCC3; Breast cancer; Calcium; Calcium signaling; Epidermal growth factor; Epithelial–mesenchymal transition