title: 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.
authors.affiliation: Vascular Biology Program, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yang
authors.forename: Brendan
authors.initials: B
authors.lastname: McNeish
authors.forename: Catherine
authors.initials: C
authors.lastname: Butterfield
authors.forename: Marsha A
authors.initials: MA
authors.lastname: Moses
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000098:blood supply*; D045744:Cell Line, Tumor; D017931:DNA Primers; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D054834:Lipocalins / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D017931:DNA Primers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C091265:Lcn3 protein, mouse; D054834:Lipocalins; D042461:Vascular Endothelial Growth Factor A