NF-κB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4

Gregory Helbig, Kent W. Christopherson, Poornima Bhat-Nakshatri, Suresh Kumar, Hiromitsu Kishimoto, Kathy D. Miller, Hal E. Broxmeyer, Harikrishna Nakshatri

Research output: Contribution to journalArticle

496 Scopus citations

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-1α (SDF-1α) 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-κB 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-κB regulates the motility of breast cancer cells by directly up-regulating the expression of CXCR4. Overexpression of the inhibitor of κB (IκB) in breast cancer cells with constitutive NF-κB activity resulted in reduced expression of CXCR4 and a corresponding loss of SDF-1α-mediated migration in vitro. Introduction of CXCR4 cDNA into IκB-expressing cells restored SDF-1α-mediated migration. Electrophoretic mobility shift assays and transient transfection assays revealed that the NF-κB 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-1α-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-1α-mediated migration was observed with cancer cells that metastasized to the lungs. Taken together, these results implicate NF-κB in the migration and the organ-specific homing of metastatic breast cancer cells.

Original languageEnglish (US)
Pages (from-to)21631-21638
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number24
DOIs
StatePublished - Jun 13 2003

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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