Inhibition of lipocalin 2 impairs breast tumorigenesis and metastasis.
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.
Leng
Xiaohong
X
Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
Ding
Tian
T
Lin
Hui
H
Wang
Yan
Y
Hu
Limei
L
Hu
Jianhua
J
Feig
Barry
B
Zhang
Wei
W
Pusztai
Lajos
L
Symmans
W Fraser
WF
Wu
Yun
Y
Arlinghaus
Ralph B
RB
D000209:Acute-Phase Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
D000209:Acute-Phase Proteins; D000071068:Lipocalin-2; D054834:Lipocalins; D020780:Matrix Metalloproteinase 9; D016328:NF-kappa B; D015513:Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C071332:Lcn2 protein, mouse