Disruption of the Lcn2 gene in mice suppresses primary mammary tumor formation but does not decrease lung metastasis
Open accessAbstract
Based largely on studies in xenograft models, lipocalin-2 (Lcn2) has been implicated in the progression of multiple types of human tumors, including breast cancer. Here we examine the role of Lcn2 in mammary tumorigenesis and lung metastasis using an in vivo molecular genetics approach. We crossed a well-characterized transgenic mouse model of breast cancer, the MMTV-PyMT (mouse mammary tumor virus-polyoma middle T antigen) mouse, with two independent gene-targeted Lcn2(-/-) mouse strains of the 129/Ola or C57BL/6 genetic background. The onset and progression of mammary tumor development and lung metastasis in the female progeny of these crosses were monitored over a 20-week period. Female Lcn2(-/-)MMTV-PyMT mice of the 129/Ola background (Lcn2(-/-)PyMT(129)) showed delayed onset of mammary tumors, and both Lcn2(-/-)PyMT(129) mice and Lcn2(-/-)MMTV-PyMT mice of the C57BL/6 background (Lcn2(-/-)PyMT(B6)) exhibited significant decreases in multiplicity and tumor burden (approximately 2- to 3-fold), as measured by total tumor weight and volume. At the molecular level, mammary tumors derived from Lcn2(-/-)PyMT(B6) females showed reduced matrix metalloproteinase-9 (MMP-9) activity and a lack of high molecular weight MMP activity. However, although increased MMP-9 activity has been linked to tumor progression, neither Lcn2(-/-)PyMT(B6) nor Lcn2(-/-)PyMT(129) female mice showed a reduction in lung metastases compared to Lcn2(+/+)PyMT controls. Our results demonstrate, using an in vivo animal model approach, that Lcn2 is a potent inducer of mammary tumor growth but not a significant promoter of lung metastasis.
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Experimental transgenic tumor-bearing mouse mammary tumor virus (PyMT) mice exhibit higher Lcn-2 plasma levels compared to controls.
“Additionally, experimental transgenic tumor-bearing mouse mammary tumor virus (PyMT) mice exhibit higher Lcn-2 plasma levels compared to controls, and Lcn-2-deficient PyMT mice developed fewer tumors than Lcn-2-competent littermates [130].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [130]
Lcn-2-deficient PyMT mice developed fewer tumors than Lcn-2-competent littermates.
“Additionally, experimental transgenic tumor-bearing mouse mammary tumor virus (PyMT) mice exhibit higher Lcn-2 plasma levels compared to controls, and Lcn-2-deficient PyMT mice developed fewer tumors than Lcn-2-competent littermates [130].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [130]
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“Additionally, experimental transgenic tumor-bearing mouse mammary tumor virus (PyMT) mice exhibit higher Lcn-2 plasma levels compared to controls, and Lcn-2-deficient PyMT mice developed fewer tumors than Lcn-2-competent littermates [130].”
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- Authors
- Berger, T., Cheung, C. C., Elia, A. J., & Mak, T. W.
- Affiliations
- University Health Network (CA)
- Corresponding author
- Mak, Tak W.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-02
- Volume
- 107
- Issue
- 7
- Pages
- 2995-3000
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2840296
- OpenAlex
- W2108346377
- Cited by
- 96
- References
- 29
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 4 · 2015: 6 · 2014: 8 · 2013: 8 · 2012: 11
- FWCI
- 3.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- 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, mammary tumor formation, lung metastasis, MMTV-PyMT mice, gene targeting, MMP-9, tumor progression, tumor suppressor
- MeSH terms
- Lipocalin-2, Acute-Phase Proteins, Animals, Crosses, Genetic, Electrophoresis, Polyacrylamide Gel, Female, Histological Techniques, Lung Neoplasms, Mice, Transgenic, Neoplasm Metastasis, Blotting, Western, Oncogene Proteins, Mammary Neoplasms, Animal, Matrix Metalloproteinase 9, Mice, Lipocalins
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