Hypoxia, Snail and incomplete epithelial-mesenchymal transition in breast cancer.

2.50
Hdl Handle:
http://hdl.handle.net/10541/91621
Title:
Hypoxia, Snail and incomplete epithelial-mesenchymal transition in breast cancer.
Authors:
Lundgren, K; Nordenskjöld, B; Landberg, Goran
Abstract:
BACKGROUND: Hypoxia is an element of the tumour microenvironment that impacts upon numerous cellular factors linked to clinical aggressiveness in cancer. One such factor, Snail, a master regulator of the epithelial-mesenchymal transition (EMT), has been implicated in key tumour biological processes such as invasion and metastasis. In this study we set out to investigate regulation of EMT in hypoxia, and the importance of Snail in cell migration and clinical outcome in breast cancer. METHODS: Four breast cancer cell lines were exposed to 0.1% oxygen and expression of EMT markers was monitored. The migratory ability was analysed following Snail overexpression and silencing. Snail expression was assessed in 500 tumour samples from premenopausal breast cancer patients, randomised to either 2 years of tamoxifen or no adjuvant treatment. RESULTS: Exposure to 0.1% oxygen resulted in elevated levels of Snail protein, along with changes in vimentin and E-cadherin expression, and in addition increased migration of MDA-MB-468 cells. Overexpression of Snail increased the motility of MCF-7, T-47D and MDA-MB-231 cells, whereas silencing of the protein resulted in decreased migratory propensity of MCF-7, MDA-MB-468 and MDA-MB-231 cells. Moreover, nuclear Snail expression was associated with tumours of higher grade and proliferation rate, but not with disease recurrence. Interestingly, Snail negativity was associated with impaired tamoxifen response (P=0.048). CONCLUSIONS: Our results demonstrate that hypoxia induces Snail expression but generally not a migratory phenotype, suggesting that hypoxic cells are only partially pushed towards EMT. Furthermore, our study supports the link between Snail and clinically relevant features and treatment response.
Affiliation:
Department of Laboratory Medicine, Center for Molecular Pathology, Malmö University Hospital, Lund University, Malmö SE-205 02, Sweden.
Citation:
Hypoxia, Snail and incomplete epithelial-mesenchymal transition in breast cancer. 2009, 101 (10):1769-81 Br. J. Cancer
Journal:
British Journal of Cancer
Issue Date:
17-Nov-2009
URI:
http://hdl.handle.net/10541/91621
DOI:
10.1038/sj.bjc.6605369
PubMed ID:
19844232
Type:
Article
Language:
en
ISSN:
1532-1827
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorLundgren, Ken
dc.contributor.authorNordenskjöld, Ben
dc.contributor.authorLandberg, Goranen
dc.date.accessioned2010-02-09T14:43:28Z-
dc.date.available2010-02-09T14:43:28Z-
dc.date.issued2009-11-17-
dc.identifier.citationHypoxia, Snail and incomplete epithelial-mesenchymal transition in breast cancer. 2009, 101 (10):1769-81 Br. J. Canceren
dc.identifier.issn1532-1827-
dc.identifier.pmid19844232-
dc.identifier.doi10.1038/sj.bjc.6605369-
dc.identifier.urihttp://hdl.handle.net/10541/91621-
dc.description.abstractBACKGROUND: Hypoxia is an element of the tumour microenvironment that impacts upon numerous cellular factors linked to clinical aggressiveness in cancer. One such factor, Snail, a master regulator of the epithelial-mesenchymal transition (EMT), has been implicated in key tumour biological processes such as invasion and metastasis. In this study we set out to investigate regulation of EMT in hypoxia, and the importance of Snail in cell migration and clinical outcome in breast cancer. METHODS: Four breast cancer cell lines were exposed to 0.1% oxygen and expression of EMT markers was monitored. The migratory ability was analysed following Snail overexpression and silencing. Snail expression was assessed in 500 tumour samples from premenopausal breast cancer patients, randomised to either 2 years of tamoxifen or no adjuvant treatment. RESULTS: Exposure to 0.1% oxygen resulted in elevated levels of Snail protein, along with changes in vimentin and E-cadherin expression, and in addition increased migration of MDA-MB-468 cells. Overexpression of Snail increased the motility of MCF-7, T-47D and MDA-MB-231 cells, whereas silencing of the protein resulted in decreased migratory propensity of MCF-7, MDA-MB-468 and MDA-MB-231 cells. Moreover, nuclear Snail expression was associated with tumours of higher grade and proliferation rate, but not with disease recurrence. Interestingly, Snail negativity was associated with impaired tamoxifen response (P=0.048). CONCLUSIONS: Our results demonstrate that hypoxia induces Snail expression but generally not a migratory phenotype, suggesting that hypoxic cells are only partially pushed towards EMT. Furthermore, our study supports the link between Snail and clinically relevant features and treatment response.en
dc.language.isoenen
dc.subjectBreast Canceren
dc.subjectCell Line Tumouren
dc.subjectBiological Tumour Markersen
dc.subject.meshBlotting, Western-
dc.subject.meshBreast Neoplasms-
dc.subject.meshCell Growth Processes-
dc.subject.meshCell Hypoxia-
dc.subject.meshCell Line, Tumor-
dc.subject.meshCell Movement-
dc.subject.meshDisease-Free Survival-
dc.subject.meshEpithelial Cells-
dc.subject.meshFemale-
dc.subject.meshHumans-
dc.subject.meshImmunohistochemistry-
dc.subject.meshKaplan-Meiers Estimate-
dc.subject.meshMesoderm-
dc.subject.meshOxygen-
dc.subject.meshSignal Transduction-
dc.subject.meshTamoxifen-
dc.subject.meshTranscription Factors-
dc.subject.meshTransfection-
dc.subject.meshTumor Markers, Biological-
dc.titleHypoxia, Snail and incomplete epithelial-mesenchymal transition in breast cancer.en
dc.typeArticleen
dc.contributor.departmentDepartment of Laboratory Medicine, Center for Molecular Pathology, Malmö University Hospital, Lund University, Malmö SE-205 02, Sweden.en
dc.identifier.journalBritish Journal of Canceren

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