Inhibition of Lipocalin 2 Impairs Breast Tumorigenesis and Metastasis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-11, Vol.69 (22), p.8579-8584
• Main Authors: XIAOHONG LENG, TIAN DING, YUN WU, ARLINGHAUS, Ralph B, HUI LIN, YAN WANG, LIMEI HU, JIANHUA HU, FEIG, Barry, WEI ZHANG, PUSZTAI, Lajos, FRASER SYMMANS, W
• Format: Article
• Language: English
• Subjects: Acute-Phase Proteins - genetics; Acute-Phase Proteins - metabolism; Animals; Antineoplastic agents; Biological and medical sciences; Blotting, Western; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Lipocalin-2; Lipocalins - genetics; Lipocalins - metabolism; Matrix Metalloproteinase 9 - blood; Medical sciences; Mice; Mice, Knockout; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; NF-kappa B - metabolism; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Pharmacology. Drug treatments; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - physiology; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-1934

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-kappaB pathway. Decreasing LCN2 expression significantly reduced the invasion and migration ability of HER2(+) 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.