MMP2 role in breast cancer brain metastasis development and its regulation by TIMP2 and ERK1/2 |
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Authors: | Odete Mendes Hun-Taek Kim Gina Lungu George Stoica |
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Institution: | (1) Department of Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843, USA |
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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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Keywords: | Brain metastases Breast cancer ERK1/2 MAPK MMP2 TIMP2 |
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