Role of MMP2, MMP3 and MMP9 in the development of breast cancer brain and lung metastasis in a syngeneic rat model
Year: 2005
Type: dissertation
Abstract: In order to study the expression of MMP2, MMP 3 and MMP9 in breast cancer\nbrain and lung metastasis, we used a syngeneic rat model of distant metastasis of\nENU1564, a carcinogen-induced mammary adenocarcinoma cell line. At six weeks post\ninoculation we observed development of micro-metastasis in the brain and lung.\nImmunohistochemistry and Western blotting analyses showed that MMP 2, -3 and -9\nprotein expression is consistently significantly higher in neoplastic brain tissue compared\nto normal brain tissue. Lung metastases express abundant MMP2, -3 and -9 in neoplastic\ncell cytoplasm. In situ zymography revealed gelatinase activity within the brain\nmetastasis. Gel zymography showed an increase in MMP2 and MMP3 activity in brain\nmetastasis. Furthermore, we were able to significantly decrease the development of breast\ncancer brain and lung metastasis in animals by treatment with PD 166793, a selective\nsynthetic MMP inhibitor. In addition, PD 166793 decreased the in vitro invasive cell\nbehavior of ENU1546. TIMP2 overexpression also decreased the development of breast\ncancer 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.\nBecause astrocytes have been associated with breast cancer brain metastasis we\nevaluated the role of astrocytes and ERK2 pathway in MMP2 up-regulation in BC brain\nmetastasis. A significant decrease in brain metastases development, and orthotopic tumor\nsize and weight were observed in animals inoculated with ENU1564-TIMP2 cells. These\nwere associated with decreased MMP2 activity, as demonstrated by gel zymography. Rat\nastrocyte-conditioned media increased expression of MMP2 in ENU15645 cells and\nincreased in vitro cell invasion of ENU1564 and ENU1564-TIMP2 cells. Blockage of\nERK1/2 phosphorylation by treatment with PD98059 decreased the expression of MMP2\nin cancer cells grown in rat astrocyte-conditioned media. We determine that MMP2 plays\na role in in vivo development of breast cancer brain metastases. Additionally, we conclude\nthat astrocytes are associated with expression of MMP2 in cancer cells via ERK1/2\nsignaling pathway.
Author: Odete Mendes
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W1453146881