Abstract
Matrix metalloproteinases (MMPs) have been implicated in diverse roles in breast cancer development and progression. While many of the different MMPs expressed in breast cancer are produced by stromal cells MMP-9 is produced mainly by the tumor cells themselves. To date, the functional role of tumor cell-produced MMP-9 has remained unclear. Here, we show that human breast cancer cell-produced MMP-9 is specifically required for invasion in cell culture and for pulmonary metastasis in a mouse orthotopic model of basal-like breast cancer. We also find that tumor cell-produced MMP-9 promotes tumor vascularization with only modest impact on primary tumor growth, and that silencing of MMP-9 expression in tumor cells leads to an altered transcriptional program consistent with reversion to a less malignant phenotype. MMP-9 is most highly expressed in human basal-like and triple negative tumors, where our data suggest that it contributes to metastatic progression. Our results suggest that MMP9 may offer a target for anti-metastatic therapies for basal-like triple negative breast cancers, a poor prognosis subtype with few available molecularly targeted therapeutic options.
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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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Blotting, Western
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Carcinoma, Basal Cell / genetics
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Carcinoma, Basal Cell / metabolism
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Carcinoma, Basal Cell / pathology*
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Cell Movement*
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Cell Proliferation*
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Disease Progression
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Female
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Humans
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Immunoenzyme Techniques
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / secondary*
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Matrix Metalloproteinase 9 / chemistry
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism*
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Neoplasm Invasiveness
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Neovascularization, Pathologic
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Oligonucleotide Array Sequence Analysis
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Triple Negative Breast Neoplasms / genetics
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Triple Negative Breast Neoplasms / metabolism
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Triple Negative Breast Neoplasms / pathology*
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Biomarkers, Tumor
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RNA, Messenger
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RNA, Small Interfering
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MMP9 protein, human
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Matrix Metalloproteinase 9