• Login
    View Item 
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UMB Digital ArchiveCommunitiesPublication DateAuthorsTitlesSubjectsThis CollectionPublication DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    Statistics

    Display statistics

    Multiple Drug Resistance-associated Protein 4 Exports the Cyclooxygenase Product Prostaglandin E2 as a Possible Mechanism to Enhance Metastasis of Basal-like Breast Cancer

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    Kochel_umaryland_0373D_10683.pdf
    Size:
    3.963Mb
    Format:
    PDF
    Download
    Author
    Kochel, Tyler Justin
    0000-0001-9185-3444
    Advisor
    Fulton, Amy M.
    Date
    2015
    Type
    dissertation
    
    Metadata
    Show full item record
    Other Titles
    Multiple Drug Resistance-associated Protein 4 Exports the Cyclooxygenase-2 Product Prostaglandin E2 as a Possible Mechanism to Enhance Metastasis of Basal-like Breast Cancer
    Abstract
    Breast cancer, like many epithelial malignancies, is frequently characterized by dysregulated levels of the enzyme cyclooxygenase 2 (COX-2). Elevated COX-2 and its major lipid product, prostaglandin E2 (PGE2), are associated with a poor prognosis in breast cancer. Targeting this inflammatory pathway with NSAIDs or selective COX-2 inhibitors has proven effective in slowing tumor progression, but has also been associated with an increased risk of adverse cardiovascular events. Multiple drug resistance-associated protein 4 (MRP4) is responsible for the active export of PGE2 from cells where this ligand binds four cognate G-protein coupled receptors (EP1-EP4) and activates multiple tumor-promoting pathways. PGE2-mediated activation of EP4 has been implicated in increased metastatic potential and support of the breast cancer stem-like phenotype. We investigated the expression and role of MRP4 in breast cancer as a possible mechanism to achieve elevated PGE2 levels in the tumor microenvironment. By evaluating publicly available breast cancer gene expression datasets and a panel of breast cancer cell lines, we report that MRP4 is expressed in breast cancer and, for the first time, that elevated expression of MRP4 is found in breast cancer subtypes (basal, HER2-enriched) with the worst prognoses. MRP4 exports PGE2 and this activity is reduced by suppressing MRP4 expression or activity through genetic or pharmacologic means. Mice bearing breast cancer xenografts with reduced expression of MRP4 developed fewer spontaneous metastases than mice bearing control tumors. The contribution of MRP4 to the metastatic cascade may be at an early step as there was no difference in trapping or colonization of cells expressing different MRP4 levels. Other members of the COX-2 pathway are implicated in support of the breast cancer stem-like cell (BCSLC) phenotype, but MRP4 expression was reduced in BCSLCs. Furthermore, altered expression of MRP4 did not significantly affect phenotypic markers of BCSLCs. In summary, elevated MRP4 is expressed in aggressive subtypes of breast cancer, is partially responsible for the level of PGE2 in the tumor microenvironment, and enhances spontaneous metastasis in an animal model. Therefore, further investigation of MRP4 as a potential therapeutic target is indicated.
    Description
    University of Maryland, Baltimore. Molecular Medicine. Ph.D. 2015
    Keyword
    COX-2
    MRP4
    prostaglandin E2
    Breast--Cancer
    Metastasis
    Dinoprostone
    Neoplasm Metastasis
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/5051
    Collections
    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Quick Guide | Policies | Contact Us | UMB Health Sciences & Human Services Library
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.