Abstract
NGAL/lipocalin-2 is a siderophore-binding protein that is highly expressed in several cancers. It is suggested to confer a proliferative advantage to cancer cells. Its expression has been correlated with aggressiveness of breast cancer as determined both in patients and in mouse breast cancer models. This was recently confirmed in two mouse models of spontaneous breast cancer in wild-type and lipocalin-2-deficient mice. We used a similar strategy using a different mouse strain. Lipocalin-2-deficient mice and mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) mice were crossed into the same FVB/N background. All mice developed tumors by week 8. The mice were sacrificed on week 13 and tissue was processed for biochemical and histological analysis. The total tumor volume and number of metastases were quantitated in 26 lipocalin-2-deficient mice and 34 wild-type controls. Lipocalin-2 expression in tumors of MMTV-PyMT-positive and wild-type mice was assessed by quantitative real-time PCR and by immunohistochemistry. The expression of the lipocalin-2 receptors 24p3R and megalin and of Mmp-9, transferrin receptor, and Bdh2 (a producer of a mammalian siderophore) were quantitated by real-time PCR. No significant difference was observed between wild-type and lipocalin-2-deficient mice. Lipocalin-2 was highly expressed in tumors from wild-type mice, but the expression did not correlate with tumor size. No effect of lipocalin-2 was observed with respect to time to tumor appearance, total tumor volume, or to the number of metastases. Histology and gelatinolytic activity of the mammary tumors did not differ between wild-type and lipocalin-2-deficient mice. We conclude that NGAL/lipocalin-2 does not invariably affect the aggressiveness of breast cancers as assessed in mouse models, thus questioning the role of lipocalin-2 in cancer development.
Highlights
NGAL, neutrophil gelatinase associated lipocalin, was so named by its discoverers as a lipocalin present in human neutrophil specific granules, in part covalently associated with gelatinase B/ matrix metalloproteinase-9 (MMP-9) [1,2]
Our results show that lipocalin-2 is dispensable for tumor development judged by any of the parameters used for determination of the clinical aggressiveness of cancers, such as differentiation grade, time to cancer development, number of mammary glands involved, size of primary tumors, and number and size of metastases in this mouse model of breast cancer induced by the mouse mammary tumor virus-polyoma middle T antigen
The first report, where tumor development was driven by the ErbB2 oncogene [39], showed both faster onset of tumor genesis, higher primary tumor numbers, larger volume of primary tumors, as well as a higher number of metastases and larger volume of metastases in lipocalin-2 expressing mice
Summary
NGAL, neutrophil gelatinase associated lipocalin, was so named by its discoverers as a lipocalin present in human neutrophil specific granules, in part covalently associated with gelatinase B/ matrix metalloproteinase-9 (MMP-9) [1,2]. The mouse orthologue was identified as an oncogene and termed 24p3 [5] but has been termed major urinary protein [6] and siderocalin [7]. These different names are united in the term lipocalin-2 encoded by the LCN2/Lcn gene in man and mouse, respectively. Soon after the discovery of lipocalin-2 as a constituent of neutrophil specific granules, lipocalin-2 was found to be highly up-regulated in epithelial cells at sites of inflammation [8,9,10] and to be highly expressed in some cancers [4,11,12,13]. A function of lipocalin-2 in the innate immune defense against bacteria was demonstrated shortly after the discovery of lipocalin-2 as a siderophore-binding protein [7,18,19], as mice deficient in lipocalin-2 are more susceptible to infections by E. coli [20,21,22], K. pneumonia [23], and M. tuberculosis [24,25] than their wild-type litter controls
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