Lipocalin 2 promotes breast cancer progression.
Here, we report that lipocalin 2 (Lcn2) promotes breast cancer progression, and we identify the mechanisms underlying this function. We first found that Lcn2 levels were consistently associated with invasive breast cancer in human tissue and urine samples. To investigate the function of Lcn2 in breast cancer progression, Lcn2 was overexpressed in human breast cancer cells and was found to up-regulate mesenchymal markers, including vimentin and fibronectin, down-regulate the epithelial marker E-cadherin, and significantly increase cell motility and invasiveness. These changes in marker expression and cell motility are hallmarks of an epithelial to mesenchymal transition (EMT). In contrast, Lcn2 silencing in aggressive breast cancer cells inhibited cell migration and the mesenchymal phenotype. Furthermore, reduced expression of estrogen receptor (ER) alpha and increased expression of the key EMT transcription factor Slug were observed with Lcn2 expression. Overexpression of ERalpha in Lcn2-expressing cells reversed the EMT and reduced Slug expression, suggesting that ERalpha negatively regulates Lcn2-induced EMT. Finally, orthotopic studies demonstrated that Lcn2-expressing breast tumors displayed a poorly differentiated phenotype and showed increased local tumor invasion and lymph node metastasis. Taken together, these in vitro, in vivo, and human studies demonstrate that Lcn2 promotes breast cancer progression by inducing EMT through the ERalpha/Slug axis and may be a useful biomarker of breast cancer.
Yang
Jiang
J
Vascular Biology Program and Department of Surgery, Children's Hospital Boston, Boston, MA 02115, USA.
Bielenberg
Diane R
DR
Rodig
Scott J
SJ
Doiron
Robert
R
Clifton
Matthew C
MC
Kung
Andrew L
AL
Strong
Roland K
RK
Zurakowski
David
D
Moses
Marsha A
MA
D000209:Acute-Phase Proteins / Q000378:metabolism* / Q000652:urine; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D004727:Endothelium / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006801:Humans; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism* / Q000652:urine; D008207:Lymphatic Metastasis; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000652:urine; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism
D000209:Acute-Phase Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors