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

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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.

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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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Acknowledgments

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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Authors and Affiliations

  1. Department of Biochemistry, Dartmouth Medical School, Hanover, NH, USA

    S. M. Eck & C. E. Brinckerhoff

  2. Department of Medicine, Norris Cotton Cancer Center, 1 Medical Center Drive, Rubin Building, HB 7936, Lebanon, NH, 03756, USA

    B. L. Petrella, C. I. Coon & C. E. Brinckerhoff

  3. Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA

    P. J. Hoopes

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  1. S. M. Eck
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  2. P. J. Hoopes
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  3. B. L. Petrella
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  4. C. I. Coon
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  5. C. E. Brinckerhoff
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Correspondence to C. E. Brinckerhoff.

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Eck, S.M., Hoopes, P.J., Petrella, B.L. et al. Matrix metalloproteinase-1 promotes breast cancer angiogenesis and osteolysis in a novel in vivo model. Breast Cancer Res Treat 116, 79–90 (2009). https://doi.org/10.1007/s10549-008-0085-3

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  • DOI: https://doi.org/10.1007/s10549-008-0085-3

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