In order to study the expression of MMP2, MMP 3 and MMP9 in breast cancer
brain and lung metastasis, we used a syngeneic rat model of distant metastasis of
ENU1564, a carcinogen-induced mammary adenocarcinoma cell line. At six weeks post
inoculation we observed development of micro-metastasis in the brain and lung.
Immunohistochemistry and Western blotting analyses showed that MMP 2, -3 and -9
protein expression is consistently significantly higher in neoplastic brain tissue compared
to normal brain tissue. Lung metastases express abundant MMP2, -3 and -9 in neoplastic
cell cytoplasm. In situ zymography revealed gelatinase activity within the brain
metastasis. Gel zymography showed an increase in MMP2 and MMP3 activity in brain
metastasis. Furthermore, we were able to significantly decrease the development of breast
cancer brain and lung metastasis in animals by treatment with PD 166793, a selective
synthetic MMP inhibitor. In addition, PD 166793 decreased the in vitro invasive cell
behavior of ENU1546. TIMP2 overexpression also decreased the development of breast
cancer lung metastasis in our model. Our results suggest that MMP2, -3 and -9 may be involved in the process of metastasis of breast cancer to the brain and lung.
Because astrocytes have been associated with breast cancer brain metastasis we
evaluated the role of astrocytes and ERK2 pathway in MMP2 up-regulation in BC brain
metastasis. A significant decrease in brain metastases development, and orthotopic tumor
size and weight were observed in animals inoculated with ENU1564-TIMP2 cells. These
were associated with decreased MMP2 activity, as demonstrated by gel zymography. Rat
astrocyte-conditioned media increased expression of MMP2 in ENU15645 cells and
increased in vitro cell invasion of ENU1564 and ENU1564-TIMP2 cells. Blockage of
ERK1/2 phosphorylation by treatment with PD98059 decreased the expression of MMP2
in cancer cells grown in rat astrocyte-conditioned media. We determine that MMP2 plays
a role in in vivo development of breast cancer brain metastases. Additionally, we conclude
that astrocytes are associated with expression of MMP2 in cancer cells via ERK1/2
signaling pathway.
| Identifer | oai:union.ndltd.org:tamu.edu/oai:repository.tamu.edu:1969.1/2645 |
| Date | 01 November 2005 |
| Creators | Mendes, Odete Rodrigues |
| Contributors | Stoica, Gheorghe |
| Publisher | Texas A&M University |
| Source Sets | Texas A and M University |
| Language | en_US |
| Detected Language | English |
| Type | Book, Thesis, Electronic Dissertation, text |
| Format | 1741925 bytes, electronic, application/pdf, born digital |
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