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

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

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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Research works printed but not linked: 2

  1. Biswas, D. K., Cruz, A. P., Gansberger, E., and Pardee, A. B. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 8542-8547
  2. Bhat-Nakshatri, P., Newton, T. R., Goulet, R., Jr., and Nakshatri, H. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 6971-6976

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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
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
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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