Inhibition of Lipocalin 2 Impairs Breast Tumorigenesis and Metastasis
Inhibition of Lipocalin 2 Impairs Breast Tumorigenesis and Metastasis
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DOI：
10.1158/0008-5472.can-09-1934
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发表时间：
2009-11-15
期刊：
影响因子：
11.2
通讯作者：
Arlinghaus, Ralph B.
中科院分区：
文献类型：
--
作者：
Leng, Xiaohong;Ding, Tian;Arlinghaus, Ralph B.
脂质运载蛋白2（LCN2；也称为中性粒细胞明胶酶相关脂质运载蛋白，NGAL）是一种分泌型糖蛋白，在乳腺癌中已观察到其表达升高。然而，LCN2在乳腺肿瘤发生中的重要性尚不清楚。在此，我们采用一种自发性乳腺肿瘤小鼠模型，结果显示缺乏小鼠LCN2的MMTV - ErbB2（V664E）小鼠乳腺肿瘤形成和转移显著延迟，血液中基质金属蛋白酶 - 9活性降低。LCN2的表达受HER2/磷脂酰肌醇3 - 激酶/AKT/NF - κB通路的上调。降低LCN2的表达显著降低了HERV乳腺癌细胞的侵袭和迁移能力。此外，向患有已形成的小鼠乳腺肿瘤的小鼠注射抗小鼠LCN2抗体导致肺转移显著受阻。我们的研究结果表明，LCN2是促进乳腺肿瘤形成和进展的关键因素，可能部分是通过稳定基质金属蛋白酶 - 9实现的。我们的结果提示，通过抑制性单克隆抗体抑制LCN2的功能对于乳腺癌治疗具有潜在价值，特别是通过干扰侵袭性乳腺癌的转移。[《癌症研究》2009年；69(22):8579 - 84]
Lipocalin 2 (LCN2; also known as NGAL) is a secreted glycoprotein and its elevated expression has been observed in breast cancers. However, the importance of LCN2 in breast tumorigenesis is unclear. Here, we employed a spontaneous mammary tumor mouse model showing that MMTV-ErbB2 (V664E) mice lacking mouse LCN2 had significantly delayed mammary tumor formation and metastasis with reduced matrix metalloproteinase-9 activity in the blood. LCN2 expression is upregulated by HER2/phosphoinositide 3-kinase/AKT/NF-kappa B pathway. Decreasing LCN2 expression significantly reduced the invasion and migration ability of HERV breast cancer cells. Furthermore, injecting an anti-mouse LCN2 antibody into mice bearing established murine breast tumors resulted in significant blockage of lung metastasis. Our findings indicate that LCN2 is a critical factor in enhancing breast tumor formation and progression possibly in part by stabilizing matrix metalloproteinase-9. Our results suggest that inhibition of LCN2 function by an inhibitory monoclonal antibody has potential for breast cancer therapy, particularly by interfering with metastasis in aggressive types of breast cancer. [Cancer Res 2009;69(22):8579-84]