Matrix metalloproteinase-1 promotes breast cancer angiogenesis and osteolysis in a novel in vivo model

  • S. M. Eck
  • P. J. Hoopes
  • B. L. Petrella
  • C. I. Coon
  • C. E. BrinckerhoffEmail author
Preclinical Study


Matrix metalloproteinase-1 (MMP-1) is critical for mediating breast cancer metastasis to bone. We investigated the role of MMP-1 in breast cancer invasion of soft tissues and bone using human MDA MB-231 breast cancer cells stably transfected with shRNAs against MMP-1 and a novel murine model of bone invasion. MMP-1 produced by breast cancer cells with control shRNA facilitated invasion of tumors into soft tissue in vivo, which correlated with enhanced blood vessel formation at the invasive edge, compared to tumors with silenced MMP-1 expression. Tumors expressing MMP-1 were also associated with osteolysis in vivo, whereas tumors with inhibited MMP-1 levels were not. Additionally, tumor-secreted MMP-1 activated bone-resorbing osteoclasts in vitro. Together, these data suggest a mechanism for MMP-1 in the activation of osteoclasts in vivo. We conclude that breast cancer-derived MMP-1 mediates invasion through soft tissues and bone via mechanisms involving matrix degradation, angiogenesis, and osteoclast activation.


Breast cancer Bone Invasion Metastasis MMP Murine model 



American Type Culture Collection


Conditioned media


Dartmouth-Hitchcock Medical Center


Human microvessel endothelial cells


Hypoxanthine-phosphoribosyl transferase


Hematoxylin and eosin




Lactalbumin hydrolysate


Local/regional recurrence


Macrophage colony stimulating factor


Matrix metalloproteins


Receptor activator of NF-κB ligand


Short hairpin RNA


Tartrate-resistant acid phosphatase



We would like to extend thanks to Dr. C. Harker Rhodes for IHC consultation and Dr. Steve Fiering for thoughtful ideas. Grant support: NIH grants AR26599 and CA77267 (C. E. Brinckerhoff) and NIH grant T32-CA009658 (S. M. Eck).


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Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • S. M. Eck
    • 1
  • P. J. Hoopes
    • 3
  • B. L. Petrella
    • 2
  • C. I. Coon
    • 2
  • C. E. Brinckerhoff
    • 1
    • 2
    Email author
  1. 1.Department of BiochemistryDartmouth Medical SchoolHanoverUSA
  2. 2.Department of MedicineNorris Cotton Cancer CenterLebanonUSA
  3. 3.Thayer School of EngineeringDartmouth CollegeHanoverUSA

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