The role of MMP-1 in breast cancer growth and metastasis to the brain in a xenograft model

Abstract

BackgroundBrain metastasis is an increasingly common complication for breast cancer patients; approximately 15– 30% of breast cancer patients develop brain metastasis. However, relatively little is known about how these metastases form, and what phenotypes are characteristic of cells with brain metastasizing potential. In this study, we show that the targeted knockdown of MMP-1 in breast cancer cells with enhanced brain metastatic ability not only reduced primary tumor growth, but also significantly inhibited brain metastasis.MethodsTwo variants of the MDA-MB-231 human breast cancer cell line selected for enhanced ability to form brain metastases in nude mice (231-BR and 231-BR3 cells) were found to express high levels of matrix metalloproteinase-1 (MMP-1). Short hairpin RNA-mediated stable knockdown of MMP-1 in 231-BR and 231-BR3 cells were established to analyze tumorigenic ability and metastatic ability.ResultsShort hairpin RNA-mediated stable knockdown of MMP-1 inhibited the invasive ability of MDA-MB 231 variant cells in vitro, and inhibited breast cancer growth when the cells were injected into the mammary fat pad of nude mice. Reduction of MMP-1 expression significantly attenuated brain metastasis and lung metastasis formation following injection of cells into the left ventricle of the heart and tail vein, respectively. There were significantly fewer proliferating cells in brain metastases of cells with reduced MMP-1 expression. Furthermore, reduced MMP-1 expression was associated with decreased TGFα release and phospho-EGFR expression in 231-BR and BR3 cells.ConclusionsOur results show that elevated expression of MMP-1 can promote the local growth and the formation of brain metastases by breast cancer cells.

Roles of the Cyclooxygenase 2 Matrix Metalloproteinase 1 Pathway in Brain Metastasis of Breast Cancer

“…In this report we have shown that MMP1 indeed promotes brain metastasis by increasing the permeability of gap junction of BBB through degradation of Claudin and Occludin. Our result is consistent with the previous observation by Liu et al (47), who showed that knockdown of MMP1 blocked primary growth and distant metastasis of breast Endothelial cells…”

The CBM Complex Underwrites NF-κB Activation to Promote HER2-Associated Tumor Malignancy

“…It has been reported that MMP1 and MMP13 are involved in breast cancer metastasis (24,25). Thus, our data indicate that NF-kB signaling contributes to cell invasiveness at least in part through MMP1 and MMP13 in HER2-positive breast cancer cells.…”

Collagen Type I as a Ligand for Receptor-Mediated Signaling

“…However, it is not clear if MMP-1 activity toward collagen type I is important for osteoblasts. While MMP-1 is not generally found to be expressed by osteoclasts, there is evidence that it may be involved in bone resorption in pathological conditions [113,116,117].…”

“…MMP-1, also known as interstitial collagenase or fibroblast collagenase, is involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and cancer metastasis [106,112,113]. Osteoblasts have been demonstrated to produce MMP-1, which may affect their differentiation [114].…”