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dc.contributor.advisorSchroeder, Joyce A.en_US
dc.contributor.authorRuss, Atlantis Dawn
dc.creatorRuss, Atlantis Dawnen_US
dc.date.accessioned2013-06-05T19:22:00Z
dc.date.available2013-06-05T19:22:00Z
dc.date.issued2013
dc.identifier.urihttp://hdl.handle.net/10150/293491
dc.description.abstractLoss of polarity is a defining characteristic of epithelial cancers. The cytoskeletal proteins, HUGL1 and HUGL2, mediate polarity in epithelial cells through diversified roles in defining membrane identity and trafficking to the basolateral membrane. Importantly, an ortholog of these molecules can inhibit tumor growth in Drosophila, although the mechanisms of their tumor suppressive functions in mammary epithelial cells are unknown. Here, we show nonredundant tumor protective roles for HUGL1 and HUGL2 in human mammary epithelial cells. Using a three dimensional culture system, we report that loss of HUGL1 or HUGL2 causes loss of apicobasal polarity, aberrant growth of multilayered epithelium, nuclear enlargement, loss of membrane identity, and cellular overgrowth. Experiments on plastic also revealed that HUGL1 or HUGL2 loss results in induction of a phenotypic EMT in breast epithelial cells and overexpression of HUGL1 in breast cancer cells reduces proliferation.In a Drosophila model of cancer driven by loss of lgl, we have discovered the consistent dysregulation of a number of miRNAs and mRNAs including the loss of let-7 and miR-9a, which are implicated in breast cancer and associated with the suppression of stem cells. Cross comparisons revealed a set of mRNAs that are both dysregulated in vivo and represent putative targets of the miRNAs changed in lgl mutants. Among these, Thrombospondin, a component of the extracellular matrix was found to be misexpressed in both flies and human cells lacking Lgl. Moreover, genetic interaction experiments showed miR-9a to be a functional effector of lgl in controlling proliferation in the wing. Taken together, the findings reported in this dissertation suggest that HUGL1 and HUGL2 function as tumor suppressors through their roles in polarity and miRNA regulation. These two proteins, functioning as modulators of cell plasticity and promoters of differentiation, are potentially able to control the transition between a differentiated epithelial cell and a cancer stem cell. This research offers new insight into the role of HUGL1 and HUGL2 in breast cancer and reveals novel targets downstream of polarity proteins for therapeutic intervention.
dc.language.isoenen_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © 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.en_US
dc.subjectHUGLen_US
dc.subjectLglen_US
dc.subjectpolarityen_US
dc.subjectGeneticsen_US
dc.subjectcancer stem cellen_US
dc.titleHUGL and the Role of Polarity in Breast Canceren_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
thesis.degree.grantorUniversity of Arizonaen_US
thesis.degree.leveldoctoralen_US
dc.contributor.committeememberZarnescu, Danielaen_US
dc.contributor.committeememberDoetschman, Tomen_US
dc.contributor.committeememberMcDermott, Kimberlyen_US
dc.contributor.committeememberSchroeder, Joyce A.en_US
dc.description.releaseRelease after 19-Oct-2013en_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineGeneticsen_US
thesis.degree.namePh.D.en_US
refterms.dateFOA2013-10-19T00:00:00Z
html.description.abstractLoss of polarity is a defining characteristic of epithelial cancers. The cytoskeletal proteins, HUGL1 and HUGL2, mediate polarity in epithelial cells through diversified roles in defining membrane identity and trafficking to the basolateral membrane. Importantly, an ortholog of these molecules can inhibit tumor growth in Drosophila, although the mechanisms of their tumor suppressive functions in mammary epithelial cells are unknown. Here, we show nonredundant tumor protective roles for HUGL1 and HUGL2 in human mammary epithelial cells. Using a three dimensional culture system, we report that loss of HUGL1 or HUGL2 causes loss of apicobasal polarity, aberrant growth of multilayered epithelium, nuclear enlargement, loss of membrane identity, and cellular overgrowth. Experiments on plastic also revealed that HUGL1 or HUGL2 loss results in induction of a phenotypic EMT in breast epithelial cells and overexpression of HUGL1 in breast cancer cells reduces proliferation.In a Drosophila model of cancer driven by loss of lgl, we have discovered the consistent dysregulation of a number of miRNAs and mRNAs including the loss of let-7 and miR-9a, which are implicated in breast cancer and associated with the suppression of stem cells. Cross comparisons revealed a set of mRNAs that are both dysregulated in vivo and represent putative targets of the miRNAs changed in lgl mutants. Among these, Thrombospondin, a component of the extracellular matrix was found to be misexpressed in both flies and human cells lacking Lgl. Moreover, genetic interaction experiments showed miR-9a to be a functional effector of lgl in controlling proliferation in the wing. Taken together, the findings reported in this dissertation suggest that HUGL1 and HUGL2 function as tumor suppressors through their roles in polarity and miRNA regulation. These two proteins, functioning as modulators of cell plasticity and promoters of differentiation, are potentially able to control the transition between a differentiated epithelial cell and a cancer stem cell. This research offers new insight into the role of HUGL1 and HUGL2 in breast cancer and reveals novel targets downstream of polarity proteins for therapeutic intervention.


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