Helbig, GregoryChristopherson, Kent W.Bhat-Nakshatri, PoornimaKumar, SureshKishimoto, HiromitsuMiller, Kathy D.Broxmeyer, Hal E.Nakshatri, Harikrishna2019-04-102019-04-102003-06-13Helbig, G., Christopherson, K. W., Bhat-Nakshatri, P., Kumar, S., Kishimoto, H., Miller, K. D., … Nakshatri, H. (2003). NF-κ B Promotes Breast Cancer Cell Migration and Metastasis by Inducing the Expression of the Chemokine Receptor CXCR4. Journal of Biological Chemistry, 278(24), 21631–21638. https://doi.org/10.1074/jbc.M3006092000021-9258, 1083-351Xhttps://hdl.handle.net/1805/18815Metastasis 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.en-USCell MigrationBreast CancerChemokine ReceptorArticle10.1074/jbc.M300609200