title: 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.
abstract: 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.
authors.affiliation: Department of Veterans Affairs, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Ueda
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Neel
authors.forename: Evemie
authors.initials: E
authors.lastname: Schutyser
authors.forename: Dayanidhi
authors.initials: D
authors.lastname: Raman
authors.forename: Ann
authors.initials: A
authors.lastname: Richmond
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D015536:Down-Regulation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008648:Mesoderm / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017434:Protein Structure, Tertiary; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D013329:Structure-Activity Relationship; D014161:Transduction, Genetic
chemical_list: D019718:Receptors, CXCR4; D020929:Mitogen-Activated Protein Kinase Kinases