Lipocalin 2 promotes breast cancer progression
Open accessAbstract
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.
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Elevated Lcn-2 levels in the urine of breast cancer patients are correlated with a poor metastatic outcome.
“Consistently, elevated Lcn-2 levels in the urine of breast cancer patients are correlated with a poor metastatic outcome [129].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [129]
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- Authors
- Yang, J., Bielenberg, D. R., Rodig, S. J., Doiron, R., Clifton, M. C., Kung, A. L., Strong, R. K., Zurakowski, D., & Moses, M. A.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Fred Hutch Cancer Center (US)
- Boston Children's Hospital (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-03-10
- Volume
- 106
- Issue
- 10
- Pages
- 3913-3918
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2656179
- OpenAlex
- W1968053635
- Cited by
- 356
- References
- 41
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 23 · 2023: 24 · 2022: 16 · 2021: 22 · 2020: 22 · 2019: 20 · 2018: 22 · 2017: 19 · 2016: 18 · 2015: 18 · 2014: 25 · 2013: 20 · 2012: 26
- FWCI
- 13.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sidney Kimmel Foundation
- National Institutes of Health
- National Cancer Institute (R01CA118764, CA118732-01A1, K01CA118732)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
- Keywords
- neutrophil gelatinase-associated lipocalin, breast cancer progression, epithelial-mesenchymal transition, estrogen receptor alpha, Slug, tumor invasion, lymph node metastasis, cell motility, E-cadherin, vimentin, fibronectin, biomarkers, urinary biomarkers
- MeSH terms
- Lipocalin-2, Snail Family Transcription Factors, Acute-Phase Proteins, Animals, Breast Neoplasms, Cell Differentiation, Cell Movement, Disease Models, Animal, Endothelium, Female, Humans, Lymphatic Metastasis, Mesoderm, Neoplasm Invasiveness, Neoplasm Staging, Phenotype, Proto-Oncogene Proteins, Transcription Factors, Disease Progression, Gene Silencing, Cell Line, Tumor, Estrogen Receptor alpha, Cell Proliferation, Mice, Lipocalins
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