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

By Gregory Helbig, K. Christopherson, P. Bhat-Nakshatri, Suresh Kumar, H. Kishimoto, K. Miller, H. Broxmeyer, Harikrishna Nakshatri. Journal of Biological Chemistry, 2003

696 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Oncology

View Paper: https://www.semanticscholar.org/paper/e512ca5896d9282b7e19f779cab755a88ba60afd

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Citations in the corpus

CXCR4–SDF-1 Signalling, Locomotion, Chemotaxis and Adhesion (2003, background): “…such as proline-rich kinase-2 (Pyk-2), p130Cas, focal adhesion kinase, paxilin, Crk and Crk-L, protein kinase C, phospholipase C-γ (PKC-γ ) as well as MAPK p42/44-ELK-1 and PI-3K-AKT-NF-κB axes (Ganju et al. 1998, Tilton et al. 2000, Chernock et al. 2001, Helbig et al. 2003, Neuhaus et al. 2003).”
Role of interleukin-6 in cancer progression and therapeutic resistance (2016, background): “breast, lung, prostate, renal carcinomas, neuroblastoma, melanoma and multiple myeloma) to the bone [141] by increasing CXCR4 expression via STAT-3 and c-Jun [142].”
CXCR4 Regulates Growth of Both Primary and Metastatic Breast Cancer (2004, background): “CXCR4 expression is up-regulated in murine lung metastases in a nuclear factor- B–dependent fashion (10), again suggesting that CXCR4 signaling is an important determinant of metastatic breast cancer.”
CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis (2006, background): “LMD231 cells were derived from MDA-MB-231 cells that had metastasized to lung from the mammary fat pad of nude mice [23].”
Tumor self-seeding by circulating cancer cells (2009, background): “(data not shown), but these cells lack IL-8 receptors (CXCR-1 and 2) (Helbig et al., 2003).”