Cited by 640Chemokine receptors and signalingNF-κB Signaling PathwaysMechanisms of cancer metastasis

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NF-κ B Promotes Breast Cancer Cell Migration and Metastasis by Inducing the Expression of the Chemokine Receptor CXCR4

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Helbig, Gregory, Christopherson, Kent W., Bhat-Nakshatri, Poornima, Kumar, Suresh, Kishimoto, Hiromitsu, Miller, Kathy D., Broxmeyer, Hal E., Nakshatri, Harikrishna·2003·Journal of Biological Chemistry

DOI 10.1074/jbc.m300609200

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Abstract

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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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
ORCID: Kumar, Suresh
Kishimoto, Hiromitsu
Miller, Kathy D.
Broxmeyer, Hal E.
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)
DOI: 10.1074/jbc.m300609200
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 6323 d)
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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NF-κ B Promotes Breast Cancer Cell Migration and Metastasis by Inducing the Expression of the Chemokine Receptor CXCR4

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