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    Functional Characterization of CXCR3 Receptor Isoforms in Breast Cancer

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    Author
    Li, Yanchun
    Advisor
    Fulton, Amy M.
    Date
    2012
    Type
    dissertation
    
    Metadata
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    Abstract
    The chemokine receptor CXCR3 belongs to the G protein-coupled receptor family. Chemokine receptors direct the trafficking of hematopoietic cells, but several are expressed on malignant cells where they play a role in tumor growth and dissemination. CXCR3 binds to the ligands CXCL9, 10, 11 and CXCL4. CXCR3 is up-regulated in breast cancers and is associated with poor prognosis, and inhibiting CXCR3 can reduce lung metastasis in a preclinical model of breast cancer. The detailed molecular mechanisms by which CXCR3 activation promotes breast cancer invasiveness remain to be clarified. In addition, the existence of two splice isoforms of CXCR3 (CXCR3-A and CXCR3-B) has made the picture more complex. In renal cell cancer, CXCR3-A has pro-neoplastic properties such as promoting proliferation and migration, whereas CXCR3-B inhibits proliferation and exerts no chemotactic effect. CXCR3-A and CXCR3-B are expressed in both normal and malignant mammary epithelial cells; CXCR3-B expression was reduced in breast cancer cell lines compared to benign cells. We hypothesize that the expression pattern shift between the two isoforms contributes to the malignant behavior of breast cancer. The purpose of the current study was to characterize the functions of CXCR3 in breast cancer cells and to determine how the shift in balance between the two isoforms affects the invasiveness of breast cancer cells. We have overexpressed and silenced expression of CXCR3-B in the highly metastatic human breast cancer cell line MDA-MB-231. Ectopic CXCR3-B expression resulted in decreased ligand-induced ERK1/2 and p38 phosphorylation, compared to enhancement of phosphorylation of the two pathways in parental MDA-MB-231 cells. Interestingly, suppression of CXCR3-B gene expression did not change the signaling response. Likewise, migratory and invasive abilities of MDA-MB-231 cells were attenuated by CXCR3-B over-expression, but not affected by CXCR3-B gene-silencing. These data suggested CXCR3-B may function to antagonize the contribution of CXCR3-A to invasiveness of cancer cells. We also identified pro-tumor activities of CXCR3-B. CXCR3-B gene expression was highly up-regulated in breast cancer stem-like cells, and overexpression of CXCR3-B supported mammosphere formation. Taken together, these data support a complex role for CXCR3-B; inhibiting the migration and invasion role of CXCR3-A but also supporting a minority population with tumor-initiating potential.
    Description
    University of Maryland in Baltimore. Molecular Medicine. Ph.D. 2012
    Keyword
    CXCR3
    isoform
    Breast--Cancer
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/2300
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    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

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