Blocking Lipocalin 2 Function Impairs Mammary Tumor Formation and Lung Metastases
T Ding, X Leng, H Lin, F Lin, B Zen, WF Symmans, K Yan, L Pusztai, RB Arlinghaus, Y Wu. University of Texas, M.D. Anderson Cancer Center, Houston, TX
Background: Breast cancer is curable in its early stage. Most cancer deaths are caused by advanced disease and distal metastases. Therefore, identifying and targeting the molecules involved in tumor progression and metastases are the key to reducing breast cancer mortality. In the current study, we identify lipocalin 2 (LCN2) as a marker of poor prognosis, demonstrate its role in tumor cell migration, invasion and metastasis in vitro and in vivo in mouse models.
Design: 318 primary breast cancer samples were analysed by Affymetrix microarray; LCN2 expression was correlated with clinical and pathological features. Xenograft models with human breast cancer cell lines with LCN2 overexpression and knockdown were established; MMTV-HER2 (V664E) transgenic mice were bred with LCN2 knockout mice to evaluate the function of LCN2 in vivo. Finally, anti-LCN2 antibody was generated and therapeutically injected into mammary tumor-bearing mice attempting to block lung metastases.
Results: Microarray analysis of 318 patient samples demonstrated that LCN2 is associated with adverse clinicopathological features (Table 1). The role of LCN2 in tumor progression was further illustrated in the xenograft mouse model and MMTV-HER2 transgenic LCN2 null mice. Human breast cancer cell lines with enforced expression of LCN2 increased tumorogenicity in nude mice. In contract, knockdown LCN2 in high expressing breast cancer cell lines reduced tumor invasion and metastases in vivo in nude mice. Deficiency of LCN2 in MMTV-HER2 transgenic mice led to impared mammary tumor formation and reduction in lung metastases. Furthermore, injecting anti-LCN2 neutralizing antibody through the tail vein significantly blocked lung metastases in mammary tumor-bearing mice.
Conclusions: LCN2 is a marker of poor prognosis in breast cancer. It plays critical roles in promoting tumor progression and metastasis. Blocking LCN2 function can block lung metastases.
Table 1. High LCN2 expression is associated with adverse clinicopathologic features.The statistical significance was identified in three analyses including Spearman's rank correlation, unequal variance t-test and Wilcox rank sum test.
|Clinicopathologic Features||Statistical Significance|
|High expression vs. low expression|
|ER - vs. ER +||p < 0.001|
|HER2 + vs. HER2 -||p < 0.05|
|Tumor stage 3 and 4 vs. 1 and 2||p < 0.02|
|Nuclear grade 3 vs. 1 and 2||p < 0.005|
|Axillary lymph node metastasis vs. non-metastasis||p < 0.01|
Tuesday, March 10, 2009 8:15 AM
Platform Session: Section G 1, Tuesday Morning