Clinical & Experimental Metastasis

, Volume 24, Issue 5, pp 341–351 | Cite as

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

  • Odete Mendes
  • Hun-Taek Kim
  • Gina Lungu
  • George StoicaEmail author
Research Paper


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.


Brain metastases Breast cancer ERK1/2 MAPK MMP2 TIMP2 



Breast cancer


Matrix metalloproteinases


Tissue inhibitors of metalloproteinases






Western blotting


Phosphate buffered saline


Central nervous system


Mitogen activated protein kinase


Glial fibrillary acidic protein


Interleukin 6


Fibroblast growth factor-b


Insulin-like growth factor


Standard deviation



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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Copyright information

© Springer Science + Business Media B.V. 2007

Authors and Affiliations

  • Odete Mendes
    • 1
  • Hun-Taek Kim
    • 1
  • Gina Lungu
    • 1
  • George Stoica
    • 1
    Email author
  1. 1.Department of Pathobiology, College of Veterinary MedicineTexas A&M UniversityCollege StationUSA

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