Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/98860
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dc.contributor.authorCursons, J.en
dc.contributor.authorLeuchowius, K.en
dc.contributor.authorWaltham, M.en
dc.contributor.authorTomaskovic-Crook, E.en
dc.contributor.authorForoutan, M.en
dc.contributor.authorBracken, C.en
dc.contributor.authorRedfern, A.en
dc.contributor.authorCrampin, E.en
dc.contributor.authorStreet, I.en
dc.contributor.authorDavis, M.en
dc.contributor.authorThompson, E.en
dc.date.issued2015en
dc.identifier.citationCell Communication and Signaling, 2015; 13(1):26-1-26-21en
dc.identifier.issn1478-811Xen
dc.identifier.issn1478-811Xen
dc.identifier.urihttp://hdl.handle.net/2440/98860-
dc.description.abstractINTRODUCTION: The normal process of epithelial mesenchymal transition (EMT) is subverted by carcinoma cells to facilitate metastatic spread. Cancer cells rarely undergo a full conversion to the mesenchymal phenotype, and instead adopt positions along the epithelial-mesenchymal axis, a propensity we refer to as epithelial mesenchymal plasticity (EMP). EMP is associated with increased risk of metastasis in breast cancer and consequent poor prognosis. Drivers towards the mesenchymal state in malignant cells include growth factor stimulation or exposure to hypoxic conditions. METHODS: We have examined EMP in two cell line models of breast cancer: the PMC42 system (PMC42-ET and PMC42-LA sublines) and MDA-MB-468 cells. Transition to a mesenchymal phenotype was induced across all three cell lines using epidermal growth factor (EGF) stimulation, and in MDA-MB-468 cells by hypoxia. We used RNA sequencing to identify gene expression changes that occur as cells transition to a more-mesenchymal phenotype, and identified the cell signalling pathways regulated across these experimental systems. We then used inhibitors to modulate signalling through these pathways, verifying the conclusions of our transcriptomic analysis. RESULTS: We found that EGF and hypoxia both drive MDA-MB-468 cells to phenotypically similar mesenchymal states. Comparing the transcriptional response to EGF and hypoxia, we have identified differences in the cellular signalling pathways that mediate, and are influenced by, EMT. Significant differences were observed for a number of important cellular signalling components previously implicated in EMT, such as HBEGF and VEGFA. We have shown that EGF- and hypoxia-induced transitions respond differently to treatment with chemical inhibitors (presented individually and in combinations) in these breast cancer cells. Unexpectedly, MDA-MB-468 cells grown under hypoxic growth conditions became even more mesenchymal following exposure to certain kinase inhibitors that prevent growth-factor induced EMT, including the mTOR inhibitor everolimus and the AKT1/2/3 inhibitor AZD5363. CONCLUSIONS: While resulting in a common phenotype, EGF and hypoxia induced subtly different signalling systems in breast cancer cells. Our findings have important implications for the use of kinase inhibitor-based therapeutic interventions in breast cancers, where these heterogeneous signalling landscapes will influence the therapeutic response.en
dc.description.statementofresponsibilityJoseph Cursons, Karl-Johan Leuchowius, Mark Waltham, Eva Tomaskovic-Crook, Momeneh Foroutan, Cameron P Bracken, Andrew Redfern, Edmund J Crampin, Ian Street, Melissa J Davis and Erik W Thompsonen
dc.language.isoenen
dc.publisherBioMed Centralen
dc.rights© 2015 Cursons et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.en
dc.subjectEpithelial mesenchymal plasticity; EMT; Metastasis; Breast cancer; EGF; Hypoxia; MEK; AKT; MDA-MB-468en
dc.titleStimulus-dependent differences in signalling regulate epithelial-mesenchymal plasticity and change the effects of drugs in breast cancer cell linesen
dc.typeJournal articleen
dc.identifier.rmid0030040580en
dc.identifier.doi10.1186/s12964-015-0106-xen
dc.identifier.pubid186551-
pubs.library.collectionMedicine publicationsen
pubs.library.teamDS08en
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
Appears in Collections:Medicine publications

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