Stimulus-dependent differences in signalling regulate epithelial-mesenchymal plasticity and change the effects of drugs in breast cancer cell lines
Cursons, Joseph, Leuchowius, Karl-Johan, Waltham, Mark, Tomaskovic-Crook, Eva, Foroutan, Momeneh, Bracken, Cameron P., Redfern, Andrew, Crampin, Edmund J., Street, Ian, Davis, Melissa J, & Thompson, Erik W. (2015) Stimulus-dependent differences in signalling regulate epithelial-mesenchymal plasticity and change the effects of drugs in breast cancer cell lines. Cell Communication and Signaling, 13, Article Number-26.
- 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.
- 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.
- 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.
- 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. © 2015 Cursons et al.; licensee BioMed Central.
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|Item Type:||Journal Article|
|Keywords:||AKT, Breast cancer, EGF, EMT, Epithelial mesenchymal plasticity, Hypoxia, MDA-MB-468, MEK, Metastasis, 1, 4 diamino 1, 4 bis(2 aminophenylthio) 2, 3 dicyanobutadiene, 2 (2 chloro 4 iodoanilino) n cyclopropylmethoxy 3, 4 difluorobenzamide, 2 (2 difluoromethylbenzimidazol 1 yl) 4, 6 dimorpholino 1, 3, 5 triazine, 2 (4 hydroxyphenyl) 4 morpholinopyrido[3', 2', 4, 5]furo[3, 2 d]pyrimidine, 4 amino n [1 (4 chlorophenyl) 3 hydroxypropyl] 1 (7h pyrrolo[2, 3 d]pyrimidin 4 yl) 4 piperidinecarboxamide, 6 (2, 6 dichlorophenyl) 8 methyl 2 (3 methylthioanilino) 8h pyrido[2, 3 d]pyrimidin 7 one, afatinib, alpha [amino(4 aminophenylthio)methylene] 2 (trifluoromethyl)phenylacetonitrile, av 412, bosutinib, dactolisib, dasatinib, epidermal growth factor, erlotinib, everolimus, gefitinib, gne 493, heparin binding epidermal growth factor, lapatinib, n (2, 3 dihydro 7, 8 dimethoxyimidazo[1, 2 c]quinazolin 5 yl)nicotinamide, n (2, 3 dihydroxypropoxy) 3, 4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide, pd 173952, pd 198306, phosphotransferase inhibitor, pictilisib, saracatinib, selumetinib, unclassified drug, unindexed drug, vandetanib, vasculotropin A, 4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo(2, 3-d)pyrimidin-4-yl)piperidine-4-carboxamide, immunosuppressive agent, MTOR protein, human, protein kinase B, pyrimidine derivative, pyrrole derivative, rapamycin, target of rapamycin kinase, Article, breast cancer cell line, cancer growth, cell hypoxia, cell transformation, controlled study, drug mechanism, epithelial mesenchymal transition, female, gene expression, human, human cell, MDA MB 468 cancer cell line, phenotype, PMC42 ET cancer cell line, PMC42 LA cancer cell line, priority journal, regulatory mechanism, RNA sequence, signal transduction, transcription initiation, analogs and derivatives, antagonists and inhibitors, breast tumor, drug effects, metabolism, pathology, tumor cell line, Breast Neoplasms, Cell Line, Tumor, Epithelial-Mesenchymal Transition, Humans, Immunosuppressive Agents, Neoplasm Metastasis, Proto-Oncogene Proteins c-akt, Pyrimidines, Pyrroles, Sirolimus, TOR Serine-Threonine Kinases|
|Subjects:||Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Cell Biology (111201)
|Divisions:||Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
|Copyright Owner:||2015 Cursons et al.; licensee BioMed Central.|
|Copyright Statement:||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.
|Deposited On:||31 Jul 2016 23:24|
|Last Modified:||02 Aug 2016 05:04|
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