Inhibition of lipocalin 2 impairs breast tumorigenesis and metastasis.

Xiaohong Leng,Ralph B Arlinghaus,W Fraser Symmans,Yun Wu,Barry Feig,Jianhua Hu,Lajos Pusztai,Yan Wang,Hui Lin,Tian Ding,Limei Hu,Wei Zhang

doi:10.1158/0008-5472.can-09-1934

Abstract

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.

Highlights

Recent studies have implicated lipocalin 2 (LCN2), a member of the lipocalin family, in leukemia [1,2,3] and other solid tumors [4]
These results indicate a role of the HER2/phosphoinositide 3-kinase/AKT/NF-κB signal cascade in inducing LCN2 expression in human breast cancer, consistent with a recent study showing that LCN2 expression was largely dependent on the NF-κB pathway in thyroid neoplastic cells [18]
The results presented here provide strong preclinical and experimental evidence that LCN2 is a critical factor that facilitates breast tumorigenesis and metastasis, and it is a potential therapeutic target for aggressive forms of breast cancer

Summary

Introduction

Recent studies have implicated lipocalin 2 (LCN2), a member of the lipocalin family, in leukemia [1,2,3] and other solid tumors [4]. The lipocalin family is a large group of small secreted glycoproteins involved in binding and transportation of small lipophilic molecules [5]. LCN2 tightly binds to bacterial iron-siderophores and deprives the iron source for their growth [6], which is shown by the delayed clearance of bacteria infection in LCN2 knockout mice [7, 8]. We found that mouse LCN2 (mLCN2) is required for BCR-ABL–induced leukemia in a mouse bone marrow transplant model and BCR-ABL+ mouse leukemic cells use the secreted LCN2 to reduce hematopoietic cells in normal bone marrow and spleen by inducing apoptosis of normal

Methods

Results

Conclusion