The Transcription Factor TCF7L2 Acts in An Isoform-Specific Manner to Regulate Epithelial Cell Plasticity: Implications for Breast Cancer Cell Invasiveness and Metastasis

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dc.contributor.advisorBonni, Shirin
dc.contributor.authorKarve, Kunal
dc.contributor.committeememberRiabowol, Karl T.
dc.contributor.committeememberSenger, Donna L.
dc.contributor.committeememberArcellana-Panlilio, Mayi Y.
dc.contributor.committeememberGoping, Ing Swie
dc.date2020-11
dc.date.accessioned2020-06-12T15:04:55Z
dc.date.available2020-06-12T15:04:55Z
dc.date.issued2020-06-05
dc.description.abstractAlternative splicing of mRNA in a mammalian cell allows generation of complexity in the proteome. The consequences of splicing and its biological significance is poorly understood in development and disease conditions. The research described in thesis investigates the biological significance of alternative splicing of the pre-mRNA of the transcription factor Transcription Factor-7 Like-2 (TCF7L2) into the three major E, S and M isoforms in epithelial and carcinoma cells. Epithelial-mesenchymal transition (EMT) is a fundamental process in development and contributes to pathological conditions including cancer. EMT contributes to cellular plasticity, as it promotes epithelial cells to attain mesenchymal features. The protein TCF7L2 regulates the proliferation and differentiation of epithelial cells, however, whether TCF7L2 acts in an isoform-dependent manner to control EMT had remained largely to be elucidated. Transforming growth factor beta (TGFβ) signaling pathway is a potent inducer of EMT in normal and cancer conditions. How TGFβ-signaling-induced EMT is controlled is the subject of much investigations. The research carried out in this thesis tests the hypothesis that TCF7L2 acts in an isoform-specific manner to differentially regulate TGFβ-induced EMT in epithelial and carcinoma cells. Gain and loss of function studies were done to determine if alterations in the protein abundance of E, M, and S TCF7L2 isoforms affects EMT induction in cells grown in the context of a three-dimensional (3D) culturing system. Our data suggest that while TCF7L2E suppresses, TCF7L2M or S promotes TGFβ-induced EMT in 3D-multicellular structures derived from non-transformed epithelial cells or carcinoma cells. In other studies, we find that TGFβ signaling reduces the proportion of TCF7L2E to TCF7L2M/S protein in cells undergoing EMT. Mechanistically, we find that TCF7L2 operates via TGFβ-Smad signaling to regulate EMT. More recent studies have also identified a specific domain in the C-terminal end of TCF7LE isoforms to be required for its ability to suppress EMT. Collectively, our findings unveil novel isoform-specific functions for the transcription factor TCF7L2 and provide novel links between TCF7L2 and TGFβ signaling in the control of EMT and potentially cancer progression.en_US
dc.identifier.citationKarve, K. (2020). The Transcription Factor TCF7L2 Acts in An Isoform-Specific Manner to Regulate Epithelial Cell Plasticity: Implications for Breast Cancer Cell Invasiveness and Metastasis (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/37907
dc.identifier.urihttp://hdl.handle.net/1880/112166
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectEpithelial-Mesenchymal-Transition (EMT)en_US
dc.subjectBreast canceren_US
dc.subjectTCF7L2 isoformsen_US
dc.subjectTGFβ signalingen_US
dc.subject.classificationBiology--Cellen_US
dc.subject.classificationBiology--Molecularen_US
dc.subject.classificationOncologyen_US
dc.subject.classificationBiochemistryen_US
dc.titleThe Transcription Factor TCF7L2 Acts in An Isoform-Specific Manner to Regulate Epithelial Cell Plasticity: Implications for Breast Cancer Cell Invasiveness and Metastasisen_US
dc.typedoctoral thesisen_US
thesis.degree.disciplineMedicine – Biochemistry and Molecular Biologyen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameDoctor of Philosophy (PhD)en_US
ucalgary.item.requestcopytrueen_US
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