title: CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways.
abstract: Aberrant expression of CXCR4 in human breast cancer correlates with metastasis to tissues secreting CXCL12. To understand the mechanism by which CXCR4 mediates breast cancer metastasis, MCF-7 breast carcinoma cells were transduced to express wild-type CXCR4 (CXCR4WT) or constitutively active CXCR4 (CXCR4ΔCTD) and analyzed in two-dimensional (2D) cultures, three-dimensional reconstituted basement membrane (3D rBM) cultures, and mice using intravital imaging. Two-dimensional cultures of MCF-7 CXCR4ΔCTD cells, but not CXCR4WT, exhibited an epithelial-to-mesenchymal transition (EMT) characterized by up-regulation of zinc finger E box-binding homeobox 1, loss of E-cadherin, up-regulation of cadherin 11, p120 isoform switching, activation of extracellular signal-regulated kinase 1/2, and matrix metalloproteinase-2. In contrast to the 2D environment, MCF-7 CXCR4WT cells cultured in 3D rBM exhibited an EMT phenotype, accompanied by expression of CXCR2, CXCR7, CXCL1, CXCL8, CCL2, interleukin-6, and granulocyte-macrophage colony stimulating factor. Dual inhibition of CXCR2 with CXCR4, or inhibition of either receptor with inhibitors of mitogen-activated protein kinase 1 or phosphatidylinositol 3-kinase, reversed the aggressive phenotype of MCF-7 CXCR4-expressing or MDA-MB-231 cells in 3D rBM. Intravital imaging of CXCR4-expressing MCF-7 cells revealed that tumor cells migrate toward blood vessels and metastasize to lymph nodes. Thus CXCR4 can drive EMT along with an up-regulation of chemokine receptors and cytokines important in cell migration, lymphatic invasion, and tumor metastasis.
authors.affiliation: Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN 37212 Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 Vanderbilt Cell Imaging Shared Resource, Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232 Division of Cancer Biostatistics, Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Tammy
authors.initials: T
authors.lastname: Sobolik
authors.forename: Ying-Jun
authors.initials: YJ
authors.lastname: Su
authors.forename: Sam
authors.initials: S
authors.lastname: Wells
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Ayers
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cook
authors.forename: Ann
authors.initials: A
authors.lastname: Richmond
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation
chemical_list: C527276:CXCR4 protein, human; D018129:Phosphatidylinositol Phosphates; D019718:Receptors, CXCR4; D023063:Receptors, Interleukin-8B