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MMP2 role in breast cancer brain metastasis development and its regulation by TIMP2 and ERK1/2

Clinical & Experimental Metastasis volume 24, pages 341–351 (2007)Cite this article

Abstract

Matrix metalloproteinase 2 (MMP2) is important in breast cancer (BC) invasion and metastasis. We previously reported that BC brain metastases, in a rat syngeneic model developed in our laboratory, have high expression and activity of MMP2. The MMP2 mechanism of action in the brain is still under intense scrutiny. To study the role of MMP2 in the development of BC brain metastasis we transfected ENU1564 rat mammary adenocarcinoma cells with tissue inhibitor of MMP2 (TIMP2). Animals inoculated with ENU1564-TIMP2 cells had decreased orthotopic tumor growth, decreased orthotopic metastastic behavior and did not develop brain metastases. These results were associated with decreased MMP2 activity, demonstrated by gel zymography. Mitogen activated protein kinase (MAPK) pathway components, such as ERK1/2, have been correlated to MMP expression and/or astrocyte activity. We found that BC brain metastases have peripheral astrocyte reactivity and higher expression of glial fibrillary acidic protein (GFAP) and phosphorylated-ERK1/2 (p-ERK1/2). Additionally, rat astrocyte-conditioned media increased in vitro invasion of ENU1564 cancer cells and increased expression of MMP2 and p-ERK1/2. Blockage of ERK1/2 phosphorylation by treatment with MEK inhibitor (PD98059) decreased the expression of MMP2 in cancer cells grown in rat astrocyte-conditioned media. Our results are highly suggestive that MMP2 plays a role in the development of BC metastases, in particular to the brain. Furthermore, our results suggest that astrocyte factors and the ERK1/2 signaling pathway may be associated with BC brain metastasis development; and that ERK1/2 may regulate MMP2 in a way that is modifiable by astrocyte factors.

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Abbreviations

BC:

Breast cancer

MMP:

Matrix metalloproteinases

TIMP:

Tissue inhibitors of metalloproteinases

BD-IV:

Berlin-Druckrey

IHC:

Immunohistochemistry

WB:

Western blotting

PBS:

Phosphate buffered saline

CNS:

Central nervous system

MAPK:

Mitogen activated protein kinase

GFAP:

Glial fibrillary acidic protein

IL6:

Interleukin 6

FGFb:

Fibroblast growth factor-b

IGF:

Insulin-like growth factor

SD:

Standard deviation

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Acknowledgments

The authors wish to thank Dr. Reza Forough, Texas A&M University, for help with data interpretation. This work was supported by a grant from National Institutes of Health (R01-NS046214-01) and the Veterinary Pathobiology Intradepartmental Ross Grant (Texas A&M University).

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  1. Department of Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, TX, 77843, USA

    Odete Mendes, Hun-Taek Kim, Gina Lungu & George Stoica

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  1. Odete Mendes
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  2. Hun-Taek Kim
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  3. Gina Lungu
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  4. George Stoica
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Correspondence to George Stoica.

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Mendes, O., Kim, HT., Lungu, G. et al. MMP2 role in breast cancer brain metastasis development and its regulation by TIMP2 and ERK1/2. Clin Exp Metastasis 24, 341–351 (2007). https://doi.org/10.1007/s10585-007-9071-0

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  • DOI: https://doi.org/10.1007/s10585-007-9071-0

Keywords

  • Brain metastases
  • Breast cancer
  • ERK1/2
  • MAPK
  • MMP2
  • TIMP2