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dc.contributor.advisorYuluğ, Işık G.en_US
dc.contributor.authorSayar, Nilüferen_US
dc.date.accessioned2016-04-29T10:42:28Z
dc.date.available2016-04-29T10:42:28Z
dc.date.copyright2015-11
dc.date.issued2015-11
dc.date.submitted17-11-2015
dc.identifier.urihttp://hdl.handle.net/11693/29015
dc.descriptionCataloged from PDF version of thesis.en_US
dc.descriptionIncludes bibliographical references (leaves 138-169).en_US
dc.descriptionThesis (Ph. D.): Bilkent University, Department of Molecular Biology and Genetics, İhsan Doğramacı Bilkent University, 2015.en_US
dc.description.abstractTumor suppressor genes (TSG) are frequently silenced in cancer by epigenetic mechanisms, including promoter DNA hypermethylation and repressive chromatin formation by means of histone deacetylation. 5-aza-2'-deoxycytidine (AZA) and Trichostatin A (TSA) are DNA methyl-transferase and histone deacetylase inhibitors, respectively, and are used as anti-cancer agents for induction of epigenetically suppressed genes. In this study, in an attempt to unmask epigenetically suppressed potential TSGs in breast cancer, two breast carcinoma cells and one non-tumorigenic breast cell line were treated with AZA and TSA, either separately or in combination, and with DMSO as control. Afterwards, highthroughput expression profiling revealed significantly affected genes and pathways in response to epigenetic induction in each cell line. Analysis of 32 candidate genes highlighted Transgelin (TAGLN) as a putative TSG that is frequently downregulated by promoter DNA hypermethylation in breast cancer cell lines, and in 61.9% of normal-paired breast tumors according to bisulfite sequencing; and in 63.02% of unpaired breast tumor tissues as determined by bioinformatics analyses of public microarray data. Both relapse-free and overall survivals of patients were more favorable with lower TAGLN methylation. Moreover, TAGLN promoter methylation levels diagnosed tumors tissues with 83.14% sensitivity and 100% specificity. qRTPCR and IHC experiments demonstrated that, TAGLN was persistently downregulated in breast cancer cell lines in comparison to non-tumorigenic cells; and in three independent sets of breast tumor tissues, compared to normal tissues. Furthermore, TAGLN expression was associated with good prognostic factors. Functional analyses in breast cancer cells revealed negative effect of transgelin on colony formation abilities of cells, and analyses with epithelial-to-mesenchymal (EMT) markers implicate an association of transgelin with EMT status of breast cancer. In short, TAGLN downregulation by promoter DNA hypermethylation in breast cancer could serve as a growth advantage to the breast cancer cells, while it could be used as a diagnostic or prognostic biomarker for breast cancer.en_US
dc.description.statementofresponsibilityby Nilüfer Sayar.en_US
dc.format.extentxvii, 184 pages : illustrations, charts.en_US
dc.language.isoEnglishen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectTAGLNen_US
dc.subjectTransgelinen_US
dc.subjectBreast canceren_US
dc.subjectMethylationen_US
dc.subjectAZAen_US
dc.subjectTSAen_US
dc.subjectBiomarkeren_US
dc.subjectEMTen_US
dc.titleUnmasking of epigenetically silenced genes and identification of transgelin as a potential methylation biomarker in breast canceren_US
dc.title.alternativeMeme kanserınde epıgenetık olarak susturulmuş genlerin açığa çıkarılması ve transgelın geninin potansiyel bir metilasyon belirteçi olarak tanımlanmasıen_US
dc.typeThesisen_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.publisherBilkent Universityen_US
dc.description.degreePh.D.en_US
dc.identifier.itemidB151762
dc.embargo.release2017-11-16


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