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NF-κ B Promotes Breast Cancer Cell Migration and Metastasis by Inducing the Expression of the Chemokine Receptor CXCR4
Open accessAbstract
Metastasis of cancer cells is a complex process involving multiple steps including invasion, angiogenesis, and trafficking of cancer cells through blood vessels, extravasations, organ-specific homing, and growth. While matrix metalloproteinases, urokinase-type plasminogen activator, and cytokines play a major role in invasion and angiogenesis, chemokines such as stromal derived factor-1alpha (SDF-1alpha) and their receptors such as CXCR4 are thought to play a critical role in motility, homing, and proliferation of cancer cells at specific metastatic sites. We and others have previously reported that the extracellular signal-activated transcription factor NF-kappaB up-regulates the expression of matrix metalloproteinases, urokinase-type plasminogen activator, and cytokines in highly metastatic breast cancer cell lines. In this report, we demonstrate that NF-kappaB regulates the motility of breast cancer cells by directly up-regulating the expression of CXCR4. Overexpression of the inhibitor of kappaB (IkappaB) in breast cancer cells with constitutive NF-kappaB activity resulted in reduced expression of CXCR4 and a corresponding loss of SDF-1alpha-mediated migration in vitro. Introduction of CXCR4 cDNA into IkappaB-expressing cells restored SDF-1alpha-mediated migration. Electrophoretic mobility shift assays and transient transfection assays revealed that the NF-kappaB subunits p65 and p50 bind directly to sequences within the -66 to +7 region of the CXCR4 promoter and activate transcription. We also show that the cell surface expression of CXCR4 and the SDF-1alpha-mediated migration are enhanced in breast cancer cells isolated from mammary fat pad xenografts compared with parental cells grown in culture. A further increase in CXCR4 cell surface expression and SDF-1alpha-mediated migration was observed with cancer cells that metastasized to the lungs. Taken together, these results implicate NF-kappaB in the migration and the organ-specific homing of metastatic breast cancer cells.
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“TMD231 cells were obtained from Dr. Harikrishna Nakshatri in 2009 and are a derivative of the MDA-MB-231 cell line (19).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [19]
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Metadata
- Authors
- Helbig, G., Christopherson, K. W., Bhat-Nakshatri, P., Kumar, S., Kishimoto, H., Miller, K. D., Broxmeyer, H. E., & Nakshatri, H.
- Affiliations
- Indiana University Indianapolis (US)
- Walther Cancer Foundation (US)
- Corresponding author
- Nakshatri, Harikrishna
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-06
- Volume
- 278
- Issue
- 24
- Pages
- 21631-21638
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1980790180
- Cited by
- 639
- References
- 42
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 15 · 2023: 12 · 2022: 19 · 2021: 14 · 2020: 23 · 2019: 18 · 2018: 33 · 2017: 28 · 2016: 34 · 2015: 30 · 2014: 35 · 2013: 42 · 2012: 18
- FWCI
- 16.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- National Institutes of Health (5r21ca082208-02)
- National Heart, Lung, and Blood Institute (HL67384, R01HL067384)
- National Cancer Institute (CA82208)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK053674, DK53674, T32DK007519)
- Topics
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- NF-κB, breast cancer, metastasis, cell migration, CXCR4, chemokine receptors, SDF-1α, chemokine signaling, IκB, transcriptional regulation, lung metastasis
- MeSH terms
- Animals, Breast Neoplasms, Cell Movement, Chemotaxis, Flow Cytometry, Genetic Vectors, Humans, Neoplasm Metastasis, Neoplasm Transplantation, Plasmids, Promoter Regions, Genetic, Ribonucleases, RNA, Messenger, Transcription, Genetic, Transfection, Tumor Cells, Cultured, Up-Regulation, Gene Expression Regulation, Neoplastic, NF-kappa B, DNA, Complementary, COS Cells, Receptors, CXCR4, Matrix Metalloproteinases, Mitogen-Activated Protein Kinases, Transcription Factor RelA, NF-kappa B p50 Subunit
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