Lipocalin 2 is a novel regulator of angiogenesis in human breast cancer

Abstract

Lipocalin 2 (Lcn2), a member of the lipocalin family, is up-regulated in a variety of epithelial cancers. We have previously reported that Lcn2 induces the epithelial to mesenchymal transition in breast cancer through the estrogen receptor α/Slug axis and that it is a potential noninvasive biomarker of this disease. Here, we report the novel finding that Lcn2 regulates breast cancer angiogenesis. Vascular endothelial growth factor (VEGF), a key angiogenic activator, was significantly increased with Lcn2 expression in MCF-7 human breast cancer cells as well as in an angiogenic line derived from MDA-MB-436 cells. Treatment with a VEGF-neutralizing antibody demonstrates that VEGF is essential for the angiogenic activity of Lcn2. We further demonstrate that Lcn2-induced VEGF is mediated through hypoxia-inducible factor 1α (HIF-1α) and that Lcn2 regulates HIF-1α through extracellular signal-regulated kinase (Erk). The regulation of HIF-1α and VEGF by Lcn2 was also demonstrated in the aggressive MDA-MB-231 cell line. Using the mouse corneal pocket assay, we found that Lcn2 significantly enhanced the angiogenesis induced by VEGF. Taken together, these results are the first to demonstrate that Lcn2 promotes angiogenesis in vitro and in vivo and suggest a novel mechanism through which Lcn2 may promote tumor progression.

Lipocalin 2 induces the epithelial–mesenchymal transition in stressed endometrial epithelial cells: possible correlation with endometriosis development in a mouse model

“…Endometriosis, such as tumorigenesis, requires angiogenesis for the ectopic mass to expand (Vargha et al 2008). As Yang's report mentioned, LCN2 may regulate angiogenesis in human breast cancer, although LCN2 levels merely correlated with vessel formation and tumor growth in breast cancer cells (Yang et al 2013). The finding supports a relationship between LCN2 and angiogenesis during the growth of endometrial tissue within the peritoneum.…”

Effect of NUCKS-1 Overexpression on Cytokine Profiling in Obese Women with Breast Cancer

“…In this sense LCN2, a newly identified biomarker and a potential therapeutic target for breast cancer, and the possible mechanisms underlying its role in tumorigenesis and metastasis as reported by Xiaohong et al (2011);Yang et al (2013).…”

“…Furthermore, their contributions to the tumor angiogenesis have been reported (Salgado et al, 2002;Yang et al, 2013). Moreover, it has been shown that treatment effectiveness and prognosis of cancer are determined by disease stage and activity of the immune system modulated by different interleukins, e.g.…”

Clinical Predictive Value of Serum Angiogenic Factor in Patients with Osteosarcoma

“…The excessive expression of VEGF has a close relationship with the growth, invasion and metastasis. A variety of experiment in vitro demonstrated that the growth factor, eg., bFGF, TGF-β1 and PDGF are able to enhance the expression and activate the capability of angiogenesis (Kasuya et al, 2011;Yang et al, 2012). The increasing of vascular density presents the accelerated speed of tumor, which could promote the metastasis of cancer.…”