Integrin alpha-2 and beta-1 expression increases through multiple generations of the EDW01 patient-derived xenograft model of breast cancer-insight into their role in epithelial mesenchymal transition in vivo gained from an in vitro model system.
Background: Breast cancers acquire aggressive capabilities via epithelial to mesenchymal transition (EMT), in which various integrins/integrin-linked kinase signalling are upregulated.Methods: We investigated this in two patient-derived xenografts (PDXs) developed from breast-to-bone metastases, and...
| Publicado en: | Breast Cancer Research Vol. 22; no. 1; pp. 1 - 22 |
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| Autores principales: | , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
BioMed Central
12/4/2020
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=147387532&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 147387532 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14655411 8UYJ jtl: Breast Cancer Research issn: 14655411 maglogo: N pubinfo: dt: 12/4/2020 vid: 22 iid: 1 pid: 24147 pub: BioMed Central artinfo: ui: 147387532 147387532 NLM33276802 147387532 10.1186/s13058-020-01366-8 NLM33276802 147387532 ppf: 1 ppct: 21 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Integrin alpha-2 and beta-1 expression increases through multiple generations of the EDW01 patient-derived xenograft model of breast cancer-insight into their role in epithelial mesenchymal transition in vivo gained from an in vitro model system. aug: au: Wafai, Razan Williams, Elizabeth D. de Souza, Emma Simpson, Peter T. McCart Reed, Amy E. Kutasovic, Jamie R. Waltham, Mark Snell, Cameron E. Blick, Tony Thompson, Erik W. Hugo, Honor J. affil: Invasion and Metastasis Unit, St. Vincent's Institute, Melbourne, VIC, Australia sug: subj: Antigens, Surface Breast Neoplasms Carcinoma, Ductal, Breast Bone Neoplasms Human Mice Biochemical Phenomena Animal Studies Female Transferases Cell Line, Tumor Breast Neoplasms Pathology Genes Breast Pathology Cell Movement Adult Genetic Techniques Comparative Studies Multicenter Studies Evaluation Research Validation Studies Clinical Assessment Tools Interview Guides Adult: 19-44 years Female ab: Background: Breast cancers acquire aggressive capabilities via epithelial to mesenchymal transition (EMT), in which various integrins/integrin-linked kinase signalling are upregulated.Methods: We investigated this in two patient-derived xenografts (PDXs) developed from breast-to-bone metastases, and its functional significance in a breast cancer cell line system. ED03 and EDW01 PDXs were grown subcutaneously in immunocompromised SCID mice through 11 passages and 7 passages, respectively. Tumour tissue was assessed using immunohistochemistry (IHC) for oestrogen receptor (ER)-alpha, E-cadherin, vimentin, Twist1, beta-catenin, P120-RasGAP, CD44, CD24 and Ki67, and RT-qPCR of EMT-related factors (CDH1, VIM, CD44, CD24), integrins beta 1 (ITGB1), alpha 2 (ITGA2) and ILK. Integrin and ILK expression in epidermal growth factor (EGF)-induced EMT of the PMC42-ET breast cancer cell line was assessed by RT-qPCR and Western blotting, as were the effects of their transient knockdown via small interfering RNA +/- EGF. Cell migration, changes in cell morphology and adhesion of siRNA-transfected PMC42-ET cells to various extracellular matrix (ECM) substrates was assessed.Results: The ED03 (ER+/PR-/HER2-/lobular) and EDW01 (ER+/PR-/HER2-/ductal) PDXs were both classified as molecular subtype luminal A. ED03 xenografts exhibited mutated E-cadherin with minimal expression, but remained vimentin-negative across all passages. In EDW01, the hypoxic indicator gene CAIX and Twist1 were co-ordinately upregulated at passages 4-5, corresponding with a decrease in E-cadherin. At passages 6-7, VIM was upregulated along with ITGB1 and ITGA2, consistent with an increasing EMT. The ED03 PDX displayed minimal change over passages in mice, for all genes examined. ILK, ITGB1 and ITGA2 mRNAs were also increased in the EGF-induced EMT of PMC42-ET cells (in which CDH1 was downregulated) although siRNA against these targets revealed that this induction was not necessary for the observed EMT. However, their knockdown significantly reduced EMT-associated adhesion and Transwell migration.Conclusion: Our data suggest that despite an increase in ITGA2 and ITGB1 gene expression in the EMT exhibited by EDW01 PDX over multiple generations, this pathway may not necessarily drive the EMT process. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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