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. Brinckerhoff
Preclinical Study

Abstract

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.

Keywords

Breast cancer Bone Invasion Metastasis MMP Murine model 

Abbreviations

ATCC

American Type Culture Collection

CM

Conditioned media

DHMC

Dartmouth-Hitchcock Medical Center

HMVECs

Human microvessel endothelial cells

HPRT

Hypoxanthine-phosphoribosyl transferase

H&E

Hematoxylin and eosin

IHC

Immunohistochemistry

LH

Lactalbumin hydrolysate

LRR

Local/regional recurrence

M-CSF

Macrophage colony stimulating factor

MMP

Matrix metalloproteins

RANKL

Receptor activator of NF-κB ligand

shRNA

Short hairpin RNA

TRAP

Tartrate-resistant acid phosphatase

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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
  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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