Journal
CANCER RESEARCH
Volume 74, Issue 23, Pages 6758-6770Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-2994
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Funding
- Fondation Contre le Cancer
- Plan Cancer
- Interuniversity Attraction Poles Programme - Belgian Science Policy
- Fonds de la Recherche Scientifique F.R.S.-FNRS
- Centre Anticancereux ULg, Belgium
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MT4-MMP (MMP-17) is a glycosylphosphatidyl inositol-anchored matrix metalloprotease expressed on the surface of cancer cells that promotes tumor growth and metastasis. In this report, we identify MT4-MMP as an important driver of cancer cell proliferation through CDK4 activation and retinoblastoma protein inactivation. We also determine a functional link between MT4-MMPand the growth factor receptor EGFR. Mechanistic experiments revealed direct association of MT4-MMPand its positive effects on EGFR phosphorylation in response to TGF alpha and EGF in cancer cells. Notably, the effects of MT4-MMP on proliferation and EGFR activation did not rely on metalloprotease activity. Clinically, MT4-MMP and EGFR expressions were correlated in human triple-negative breast cancer specimens. Altogether, our results identify MT4-MMP as a positive modifier of EGFR outside-in signaling that acts to cooperatively drive cancer cell proliferation. (C) 2014 AACR.
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