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

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 metastatic 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.

Mesenchymal Stem Cells Overexpressing IFN-β Inhibit Breast Cancer Growth and Metastases through Stat3 Signaling in a Syngeneic Tumor Model

“…Furthermore, the inactivation of Stat3 leads to decreased expression of c-Myc and MMP2. Because c-Myc has been characterized as a potent factor for cell proliferation (46) and MMP2 is closely associated with cancer invasion and metastasis (47), it is possible that these combined effects contribute to the observed growth and metastasis inhibition of breast cancer in mice.…”

Functions of epidermal growth factor receptor in cisplatin response of thyroid cells

“…Whereas ERK predominantly confers survival advantage to cells during most stress conditions in various types of cells, p38 is associated with cell death [9]. Several signalling transduction pathways activated by cisplatin, such as the MAPK pathway components, have been correlated to matrix metalloproteinases (MMPs) activation and expression [10]; furthermore, the anti-invasive properties of cisplatin associated with decrease in MMPs activity have also been reported [11]. Stimulation of MMPs production in some cancer cells appeared to be EGFR-dependent [12], whilst, on the other hand, among multiple mechanisms for EGFR transactivation, the autocrine/paracrine release of soluble EGF A c c e p t e d M a n u s c r i p t…”

Transcriptional Repression of Mad-Max Complex by Human Umbilical Cord Blood Stem Cells Downregulates Extracellular Signal-Regulated Kinase in Glioblastoma

“…Accumulating evidence from various studies suggest the potential role of the ERK pathway in the migration of various cell types, and that the activation of ERK contributes to the progression of tumors through transcriptional regulation of metastasis-related genes [25,26]. The ERK inhibitor PD98059 suppressed the proliferation of glioma C6 cells indicating that activation of ERK was integral to the invasion/migration of human chondrosarcoma cells [27] and U87 glioma cells [28].…”