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 invas…
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Hypoxia and HIFs can induce tumor cell invasion and degradation of the extracellular matrix via mechanisms including upregulation of cathepsin D, urokinase-type plasminogen activator receptor, and matrix metalloproteinases-1 and -2 and activation of Met.
“Hypoxia and HIFs can also induce tumor cell invasion and degradation of the extracellular matrix via various mechanisms including upregulation of cathepsin D, urokinase-type plasminogen activator receptor, and matrix metalloproteinases-1 and -2 (Krishnamachary et al., 2003;Munoz-Najar et al., 2006) and activation of Met (Pennacchietti et al., 2003).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Munoz-Najar et al., 2006
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“and matrix metalloproteinases-1 and -2 (Krishnamachary et al., 2003; Munoz-Najar et al., 2006) and activation of Met (Pennacchietti et al.”
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Singleton, D. C., Rouhi, P., Zois, C. E., Haider, S., Li, J.-L., Kessler, B. M., Cao, Y., & Harris, A. L. (2015) · Oncogene · doi:10.1038/onc.2014.396 · Cited by 52 · see citing works
- Authors
- Muñoz-Nájar, U. M., Neurath, K. M., Vumbaca, F., & Claffey, K. P.
- Affiliations
- UConn Health (US)
- Corresponding author
- Claffey, K P
- ORCID
- Claffey, K P
- Venue
- Oncogene
- Published
- 2005-12-12
- Volume
- 25
- Issue
- 16
- Pages
- 2379-2392
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2080619157
- Cited by
- 209
- References
- 3
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 7 · 2023: 16 · 2022: 13 · 2021: 11 · 2020: 13 · 2019: 8 · 2018: 9 · 2017: 10 · 2016: 5 · 2015: 11 · 2014: 12 · 2013: 11 · 2012: 12
- FWCI
- 3.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA 64436)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- hypoxia, breast cancer, tumor invasion, MT1-MMP, MMP-2 activation, matrix metalloproteinases, extracellular matrix degradation, TIMP-2, RhoA, hypoxic tumor microenvironment, MDA-MB-231 cells, MDA-MB-435
- MeSH terms
- Breast Neoplasms, Enzyme Activation, Female, Humans, Neoplasm Invasiveness, RNA, Messenger, Cell Hypoxia, Tissue Inhibitor of Metalloproteinase-2, rhoA GTP-Binding Protein, Matrix Metalloproteinase 2, Matrix Metalloproteinases, RNA Interference, Cell Line, Tumor, Matrix Metalloproteinases, Membrane-Associated
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