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Hypoxia as a hallmark of the cancer microenvironment induces epithelial-mesenchymal transition (EMT) in breast cancer cells, a process whereby cancer cells acquire a more invasive phenotype. We have recently characterised the remodelling of calcium (Ca²⁺) signalling as a consequence of EMT induced by epidermal growth factor (EGF). In this study we aimed to characterise the remodelling of Ca²⁺ signalling in a model of hypoxia-induced EMT in MDA-MB-468 breast cancer cells. The induction of EMT by hypoxia (1% O₂) was confirmed by assessing the protein level of vimentin (after 48 h hypoxia) and mRNA levels of some of other EMT markers including vimentin, Snail, Twist, N-cadherin and the CD44/CD24 ratio (after 24 h hypoxia). The mRNA levels of fifty Ca²⁺ pumps, Ca 2+ channels and receptors in the presence and absence of hypoxia (24 h) were assessed using real time RT-PCR. This led to identification of four specific targets which were significantly up-regulated in hypoxia compared to normoxia (21% O₂), including P2Y6. This purinergic receptor, showed a three-fold mRNA induction by hypoxia. Pharmacological inhibition of P2Y6 by its selective inhibitor MRS2578, significantly reduced cellular migration of the mesenchymal like MDA-MB-231 breast cancer cell line. Gene expression profiling of 458 breast tumours revealed elevation of P2Y6 in basal breast cancer subtypes compared to other subtypes. Furthermore, breast cancer patients with high P2Y6 levels showed reduced overall survival rates compared to patients with low levels of P2Y6 (total patient number = 1115, P-value = 0.019). In conclusion, alterations in Ca²⁺ signalling and P2Y6 purinergic receptor expression is a feature of hypoxia-induced EMT. Further studies are required to identify if a specific Ca²⁺pump, Ca²⁺ channel or receptor may represent a target for the mesenchymal phenotype of breast cancer cells and offer a therapeutic strategy for the control of breast cancer metastasis.

Item Type:	Conference Extract
Keywords:	Calcium signalling, hypoxia, EMT, breast cancer
Research Division:	Biomedical and Clinical Sciences
Research Group:	Pharmacology and pharmaceutical sciences
Research Field:	Basic pharmacology
Objective Division:	Expanding Knowledge
Objective Group:	Expanding knowledge
Objective Field:	Expanding knowledge in the health sciences
UTAS Author:	Azimi, I (Dr Iman Azimi)
ID Code:	151221
Year Published:	2014
Deposited By:	Pharmacy
Deposited On:	2022-07-25
Last Modified:	2022-07-28
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