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.
Highlights
Breast cancer is the most frequently diagnosed cancer in women in the United States, and accounts for the second highest number of cancer deaths [1]
We have previously found that tumors derived from MDA-MB-231 human breast cancer cells orthotopically implanted in mice show evidence of gelatinase activity, and that treatment of MDA-MB-231 cells with tissue inhibitor of metalloproteinases-1 (TIMP-1) can reduce cellular invasiveness [29]
Hypothesizing that Matrix metalloproteinase 9 (MMP9) may act as a general driver of the invasive/metastatic propensities of triple negative breast cancers, we evaluated the impact of MMP9 knockdown on basal-like, triple negative breast cancer cell lines BT-549 and SUM159PT
Summary
Breast cancer is the most frequently diagnosed cancer in women in the United States, and accounts for the second highest number of cancer deaths [1]. Triple negative or basal-like cancers are more often highly invasive, spreading to lymph nodes while primary tumors are still small, and leading to early relapse with distant metastasis [9,10,11]. Outlooks for these high risk groups can be improved by unraveling the mechanisms that enable uncontrolled cancer spread, and by identifying new points of therapeutic intervention for those breast cancer subtypes that are refractory to currently available molecularly targeted therapies
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