Role of MMP2 in Brain Metastasis
Matrix metalloproteinase 2 (MMP2) is important in breast cancer (BC) invasion and metastasis.
In order to study the expression of MMP2, in breast cancer brain metastasis, we used a syngeneic rat model of distant metastasis of ENU1564, a carcinogen-induced mammary adenocarcinoma cell line. At 6 weeks post left-ventricle inoculation we observed development of micro-metastasis in the brain. Immunohistochemistry (IHC) and Western blotting (WB) analyses showed that MMP2 protein expressions were significantly higher in neoplastic brain tissue compared to normal brain tissue. These results were confirmed by RT-PCR and gelatin zymography increased in MMP2 and activity in brain metastasis. 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. 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). 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.
KeywordsBreast Cancer Brain Metastasis Glial Fibrillary Acidic Protein MMP2 Expression Mitogen Activate Protein Kinase Pathway
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