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Inhibition of Lipocalin 2 Impairs Breast Tumorigenesis and Metastasis

Departments of ¹ Molecular Pathology, ² Pathology, ³ Biostatistics, ⁴ Surgical Oncology, and ⁵ Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Ralph B. Arlinghaus, Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Unit 951, 7435 Fannin Street, Houston, TX 77054. Phone: 713-792-8995; Fax: 713-834-6082; E-mail: rarlingh{at}mdanderson.org and Yun Wu, Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Unit 085, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-563-1847; Fax: 713-563-1848; E-mail: YunWu{at}mdanderson.org.

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-B 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. [Cancer Res 2009;69(22):8579–84]

Key Words: lipocalin 2 • NGAL • breast cancer • metastasis