Deletion of the COOH-terminal domain of CXC chemokine receptor 4 leads to the down-regulation of cell-to-cell contact, enhanced motility and proliferation in breast carcinoma cells.

Ueda Y, Neel NF, Schutyser E, Raman D, Richmond A
Cancer Res. 2006 66 (11): 5665-75

PMID: 16740704 · PMCID: PMC2664111 · DOI:10.1158/0008-5472.CAN-05-3579

The CXC chemokine receptor 4 (CXCR4) contributes to the metastasis of human breast cancer cells. The CXCR4 COOH-terminal domain (CTD) seems to play a major role in regulating receptor desensitization and down-regulation. We expressed either wild-type CXCR4 (CXCR4-WT) or CTD-truncated CXCR4 (CXCR4-DeltaCTD) in MCF-7 human mammary carcinoma cells to determine whether the CTD is involved in CXCR4-modulated proliferation of mammary carcinoma cells. CXCR4-WT-transduced MCF-7 cells (MCF-7/CXCR4-WT cells) do not differ from vector-transduced MCF-7 control cells in morphology or growth rate. However, CXCR4-DeltaCTD-transduced MCF-7 cells (MCF-7/CXCR4-DeltaCTD cells) exhibit a higher growth rate and altered morphology, potentially indicating an epithelial-to-mesenchymal transition. Furthermore, extracellular signal-regulated kinase (ERK) activation and cell motility are increased in these cells. Ligand induces receptor association with beta-arrestin for both CXCR4-WT and CXCR4-DeltaCTD in these MCF-7 cells. Overexpressed CXCR4-WT localizes predominantly to the cell surface in unstimulated cells, whereas a significant portion of overexpressed CXCR4-DeltaCTD resides intracellularly in recycling endosomes. Analysis with human oligomicroarray, Western blot, and immunohistochemistry showed that E-cadherin and Zonula occludens are down-regulated in MCF-7/CXCR4-DeltaCTD cells. The array analysis also indicates that mesenchymal marker proteins and certain growth factor receptors are up-regulated in MCF-7/CXCR4-DeltaCTD cells. These observations suggest that (a) the overexpression of CXCR4-DeltaCTD leads to a gain-of-function of CXCR4-mediated signaling and (b) the CTD of CXCR4-WT may perform a feedback repressor function in this signaling pathway. These data will contribute to our understanding of how CXCR4-DeltaCTD may promote progression of breast tumors to metastatic lesions.

MeSH Terms (18)

Breast Neoplasms Cell Communication Cell Growth Processes Cell Line, Tumor Cell Movement Down-Regulation Enzyme Activation Epithelial Cells Genetic Vectors Humans Mesoderm Mitogen-Activated Protein Kinase Kinases Oligonucleotide Array Sequence Analysis Protein Structure, Tertiary Receptors, CXCR4 Retroviridae Structure-Activity Relationship Transduction, Genetic

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