Abstract
Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor that is not expressed in normal breast epithelia but is up-regulated in invasive breast carcinomas. In the present study, we found that matrix metalloprotease-1 (MMP-1) robustly activates the PAR1-Akt survival pathway in breast carcinoma cells. This process is blocked by a cell-penetrating lipopeptide "pepducin," P1pal-7, which is a potent inhibitor of cell viability in breast carcinoma cells expressing PAR1. Both a MMP-1 inhibitor and P1pal-7 significantly promote apoptosis in breast tumor xenografts and inhibit metastasis to the lungs by up to 88%. Dual therapy with P1pal-7 and Taxotere inhibits the growth of MDA-MB-231 xenografts by 95%. Consistently, biochemical analysis of xenograft tumors treated with P1pal-7 or MMP-1 inhibitor showed attenuated Akt activity. Ectopic expression of constitutively active Akt rescues breast cancer cells from the synergistic cytotoxicity of P1pal-7 and Taxotere, suggesting that Akt is a critical component of PAR1-dependent cancer cell viability. Together, these findings indicate that blockade of MMP1-PAR1 signaling may provide a benefit beyond treatment with Taxotere alone in advanced, metastatic breast cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / administration & dosage
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Apoptosis / drug effects
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / enzymology
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Caspases / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / physiology
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Docetaxel
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Drug Synergism
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Enzyme Activation
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Female
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Humans
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Lung Neoplasms / metabolism
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Lung Neoplasms / secondary
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Matrix Metalloproteinase 1 / metabolism
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Matrix Metalloproteinase Inhibitors
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Mice
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Mice, Nude
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Peptides / administration & dosage
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Peptides / pharmacokinetics
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Peptides / pharmacology*
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / genetics
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Receptor, PAR-1 / antagonists & inhibitors*
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Receptor, PAR-1 / genetics
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Receptor, PAR-1 / metabolism
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Signal Transduction / drug effects
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Taxoids / administration & dosage
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Xenograft Model Antitumor Assays
Substances
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Matrix Metalloproteinase Inhibitors
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Peptides
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RNA, Small Interfering
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Receptor, PAR-1
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Taxoids
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Docetaxel
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Proto-Oncogene Proteins c-akt
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Caspases
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MMP1 protein, human
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Matrix Metalloproteinase 1