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    Analysis of Integrin α6β4 Function in Breast Carcinoma: A Dissertation

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    Authors
    Gerson, Kristin D.
    Faculty Advisor
    Arthur M. Mercurio PhD
    Academic Program
    MD/PhD
    UMass Chan Affiliations
    Molecular, Cell and Cancer Biology
    Document Type
    Doctoral Dissertation
    Publication Date
    2012-04-06
    Keywords
    Breast Neoplasms
    Integrin alpha6beta4
    Cell Movement
    MicroRNAs
    Neoplasm Invasiveness
    Amino Acids, Peptides, and Proteins
    Cancer Biology
    Neoplasms
    Nucleic Acids, Nucleotides, and Nucleosides
    Skin and Connective Tissue Diseases
    
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    Abstract
    The development and survival of multicellular organisms depends upon the ability of cells to move. Embryogenesis, immune surveillance, wound healing, and metastatic disease are all processes that necessitate effective cellular locomotion. Central to the process of cell motility is the family of integrins, transmembrane cell surface receptors that mediate stable adhesions between cells and their extracellular environment. Many human diseases are associated with aberrant integrin function. Carcinoma cells in particular can hijack integrins, harnessing their mechanical and signaling potential to propagate cell invasion and metastatic disease, one example being integrin α6β4. This integrin, often referred to simply as β4, is defined as an adhesion receptor for the laminin family of extracellular matrix proteins. The role of integrin β4 in potentiating carcinoma invasion is well established, during which it serves both a mechanical and signaling function. miRNAs are short non-coding RNAs that regulate gene expression posttranscriptionally, and data describing the role of extracellular stimuli in governing their expression patterns are sparse. This observation coupled to the increasingly significant role of miRNAs in tumorigenesis prompted us to examine their function as downstream effectors of β4, an integrin closely linked to aggressive disease in breast carcinoma. The work presented in this dissertation documents the first example that integrin expression correlates with specific miRNA patterns. Moreover, integrin β4 status in vitro and in vivo is associated with decreased expression of distinct miRNA families in breast cancer, namely miR-25/32/92abc/363/363-3p/367 and miR-99ab/100, with purported roles in cell motility. Another miRNA, miR-29a, is significantly downregulated in response to de novo expression of β4 in a breast carcinoma cell line, and β4-mediated repression of the miRNA is required for invasion. Another major conclusion of this study is that β4 integrin expression and ligation can regulate the expression of SPARC in breast carcinoma cells. These data reveal distinct mechanisms by which β4 promotes SPARC expression, involving both a miR-29a-mediated process and a TOR-dependent translational mechanism. Our observations establish a link between miRNA expression patterns and cell motility downstream of β4 in the context of breast cancer, and uncover a novel effector of β4-mediated invasion.
    DOI
    10.13028/1pw6-cg18
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31932
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/1pw6-cg18
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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