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Open Access Highly Accessed Research article

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

Hui Liu1*, Yukinari Kato1, Stephanie A Erzinger1, Galina M Kiriakova1, Yongzhen Qian2, Diane Palmieri2, Patricia S Steeg2 and Janet E Price1*

Author affiliations

1 Department of Cancer Biology, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, 77030, USA

2 Women’s Cancers Section, Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, MD, 20892, USA

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Citation and License

BMC Cancer 2012, 12:583  doi:10.1186/1471-2407-12-583

Published: 7 December 2012

Abstract

Background

Brain 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.

Methods

Two 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.

Results

Short 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.

Conclusions

Our results show that elevated expression of MMP-1 can promote the local growth and the formation of brain metastases by breast cancer cells.

Keywords:
Breast cancer; Brain metastasis; MMP-1; TGFα; EGFR