• Login
    View Item 
    •   Home
    • UA Graduate and Undergraduate Research
    • UA Theses and Dissertations
    • Dissertations
    • View Item
    •   Home
    • UA Graduate and Undergraduate Research
    • UA Theses and Dissertations
    • Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UA Campus RepositoryCommunitiesTitleAuthorsIssue DateSubmit DateSubjectsPublisherJournalThis CollectionTitleAuthorsIssue DateSubmit DateSubjectsPublisherJournal

    My Account

    LoginRegister

    About

    AboutUA Faculty PublicationsUA DissertationsUA Master's ThesesUA Honors ThesesUA PressUA YearbooksUA CatalogsUA Libraries

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    DETERMINING THE ROLE OF MUC1 AND BETA-CATENIN ON THE EPIDERMAL GROWTH FACTOR RECEPTOR SIGNALING AND LOCALIZATION IN BREAST CANCER

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    azu_etd_11057_sip1_m.pdf
    Size:
    6.121Mb
    Format:
    PDF
    Description:
    azu_etd_11057_sip1_m.pdf
    Download
    Author
    Bitler, Benjamin Guy
    Issue Date
    2010
    Keywords
    beta-catenin
    breast cancer
    EGFR
    MUC1
    Nuclear Localization
    Trafficking
    Advisor
    Schroeder, Joyce A.
    Committee Chair
    Schroeder, Joyce A.
    
    Metadata
    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    The epidermal growth factor family of receptors is important in the development and progression of many types of cancers including, breast, lung, and glioblastoma. The family consists of 4 members (EGFR/erbB1, Her2/erbB2, erbB3, and erbB4). In all breast cancer cases, EGFR expression is deregulated 20 to 30% of the time; however in the most aggressive form of breast cancer (basal-like) EGFR expression is upregulated in 60% of cases. EGFR's expression and activity can be altered in transformed cells through a variety of mechanisms, such as novel protein-protein interactions, gene amplification, mutations, and loss of regulatory proteins. In this work we have examined the role of cancer specific protein interactions of EGFR with MUC1 and beta-catenin in the progression of breast cancer.Herein I report that the interaction of MUC1 and EGFR in breast cancer cells alters EGFR localization by promoting EGFR nuclear translocation. Importantly, I discovered that the presence of MUC1 mediates EGFR's interaction with chromatin. More specifically, I found that EGFR interacts with the cyclin D1 promoter region in a MUC1-dependent fashion which resulted in a significant increase in cyclin D1 protein expression. Nuclear EGFR localization has been shown to correlate with resistance to anti-EGFR therapies, which indicates that MUC1's interaction with EGFR could be a mechanism of resistance.MUC1's interaction with both EGFR and beta-catenin can promote transformation therefore a peptide therapy was developed, PMIP, which mimics the hypothesized interaction domains of MUC1's cytoplasmic tail. PMIP was designed to inhibit the interaction of MUC1/EGFR and MUC1/beta-catenin thereby regulating EGFR expression and promoting beta-catenin localization to adherens junctions. PMIP effectively enters the cytosol of cells and inhibits the target interactions. Importantly, PMIP inhibited invasion and proliferation of breast cancer cells and in mice significantly reduced the growth rate of breast cancer xenograft and genetically-driven tumors. This study demonstrated that the use of peptides to inhibit intracellular protein interactions is a viable option that would have limited toxic side-effects. Overall, this work reveals a new regulatory role of EGFR localization and activity by MUC1 and that this mechanism is viable therapeutic breast cancer target.Lastly, in a mouse model of breast cancer I examined the role of EGFR tyrosine kinase activity in beta-catenin dependent tumorigenesis. A transgenic mouse model of breast cancer, MMTV-Wnt-1, was bred onto an EGFR kinase deficient background. I discovered that the loss of EGFR kinase activity in this model resulted in a significant delay in tumor onset and inhibited tumor growth. These findings indicate a cooperation of EGFR and beta-catenin dependent signaling pathways, which promote transformation of glandular epithelial cells.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Cancer Biology
    Graduate College
    Degree Grantor
    University of Arizona
    Collections
    Dissertations

    entitlement

     
    The University of Arizona Libraries | 1510 E. University Blvd. | Tucson, AZ 85721-0055
    Tel 520-621-6442 | repository@u.library.arizona.edu
    DSpace software copyright © 2002-2017  DuraSpace
    Quick Guide | Contact Us | Send Feedback
    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.