Department of Cancer Biology, The University of Texas, MD, Anderson Cancer Center, Houston, TX 77030, USA.
BMC Cancer. 2012 Dec 7;12:583. doi: 10.1186/1471-2407-12-583.
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.
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.
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.
Our results show that elevated expression of MMP-1 can promote the local growth and the formation of brain metastases by breast cancer cells.
脑转移是乳腺癌患者越来越常见的并发症；约 15-30%的乳腺癌患者会发生脑转移。然而，人们对这些转移是如何形成的，以及具有脑转移潜能的细胞有哪些特征性表型知之甚少。在这项研究中，我们表明，靶向敲低具有增强脑转移能力的乳腺癌细胞中的 MMP-1，不仅降低了原发肿瘤的生长，还显著抑制了脑转移。
两种选择用于增强裸鼠脑转移能力的 MDA-MB-231 人乳腺癌细胞系（231-BR 和 231-BR3 细胞）被发现表达高水平的基质金属蛋白酶-1（MMP-1）。建立短发夹 RNA 介导的 231-BR 和 231-BR3 细胞中 MMP-1 的稳定敲低，以分析肿瘤发生能力和转移能力。
短发夹 RNA 介导的 MMP-1 稳定敲低抑制了 MDA-MB 231 变体细胞在体外的侵袭能力，并抑制了细胞注射到裸鼠乳腺脂肪垫时的乳腺癌生长。MMP-1 表达的减少显著减弱了细胞注射到心脏左心室和尾静脉后形成脑转移和肺转移的能力。表达减少 MMP-1 的脑转移中增殖细胞明显减少。此外，在 231-BR 和 BR3 细胞中，MMP-1 表达的减少与 TGFα 释放和磷酸化 EGFR 表达的减少有关。
我们的结果表明，MMP-1 的高表达可以促进乳腺癌细胞的局部生长和脑转移的形成。
