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Br J Cancer. 2009 Nov 17;101(10):1769-81. doi: 10.1038/sj.bjc.6605369. Epub 2009 Oct 20.

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

Author information

1
Department of Laboratory Medicine, Center for Molecular Pathology, Malmö University Hospital, Lund University, Malmö SE-205 02, Sweden.

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.

PMID:
19844232
PMCID:
PMC2778529
DOI:
10.1038/sj.bjc.6605369
[Indexed for MEDLINE]
Free PMC Article

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