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  • Original Article
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Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation

Abstract

The process of cancer cell invasion involves degradation of the extracellular matrix (ECM) by proteases, integrin adhesion and cell motility. The role of ECM degrading proteases on the hypoxia-induced invasion of breast carcinoma cells was investigated. Hypoxia markedly increased the invasion capacity of MDA-MB-231 and MDA-MB-435 breast carcinoma cell lines. Matrix metalloproteinase (MMP) inhibitors blocked the hypoxia-induced invasion, whereas other protease inhibitors had no effect. Antibodies or siRNAs blocking either membrane type-1 MMP (MT1-MMP) or MMP-2 were effective in reducing the hypoxia-induced invasion. Serum-free reconstitution experiments confirmed the involvement of the MT1-MMP/MMP-2/tissue inhibitor of metalloproteinase-2 complex in this hypoxia-induced response. Overexpression of MT1-MMP in a poorly invasive breast cancer cell line, T47-D, promoted hypoxia-induced invasion and MMP-2 activation. Cell surface accumulation and activation of MT1-MMP without apparent regulation at the mRNA or protein levels indicated a post-translational adaptive response to hypoxia. Inhibition of the small GTPase RhoA eliminated the hypoxia-induced invasion and blocked the localization of MT1-MMP to the plasma membrane. Zymographic and molecular analysis of human breast tumors showed a strong correlation between hypoxic microenvironments and MMP-2 activation without changes in MT1-MMP expression. Our studies suggest that hypoxic tumor microenvironments promote breast cancer invasion through an MT1-MMP-dependent mechanism.

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Acknowledgements

We greatly appreciate the assistance provided by Dr Art Hand and David Serwanski of the Electron Microscopy Core. We would also like to thank Dr Teresa Sanchez from the Center for Vascular Biology for kindly providing the reagents needed for the small GTPases experiments. We greatly appreciate the contributions of Anshu Agarwal, Martin Keough and Tatiana Estrada-Hernandez for early observations, helpful discussions and technical support. This work was supported by NIH: NCI CA64436 and the Patrick and Catherine Weldon Donaghue Foundation.

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Correspondence to K P Claffey.

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Muñoz-Nájar, U., Neurath, K., Vumbaca, F. et al. Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation. Oncogene 25, 2379–2392 (2006). https://doi.org/10.1038/sj.onc.1209273

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