Oncotarget

Research Papers:

Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer

Christine Mehner _, Alexandra Hockla, Erin Miller, Sophia Ran, Derek C. Radisky and Evette S. Radisky

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Oncotarget. 2014; 5:2736-2749. https://doi.org/10.18632/oncotarget.1932

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Abstract

Christine Mehner1, Alexandra Hockla1, Erin Miller1, Sophia Ran2, Derek C. Radisky1,* and Evette S. Radisky1,*

1 Department of Cancer Biology, Mayo Clinic, Jacksonville, FL

2 Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL

Correspondence:

Evette S. Radisky, email:

Derek C. Radisky, email:

Keywords: triple negative breast cancer, basal-like breast cancer, matrix metalloproteinases, invasion, metastasis, mouse orthotopic tumor models, bioluminescence imaging

Received: March 3, 2014 Accepted: April 30, 2014 Published: May 1, 2014

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.


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PII: 1932