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dc.contributor.advisorŞahin, Özgür
dc.contributor.authorBal, Hilal
dc.date.accessioned2017-09-18T13:26:45Z
dc.date.available2017-09-18T13:26:45Z
dc.date.copyright2017-09
dc.date.issued2017-09
dc.date.submitted2017-09-15
dc.identifier.urihttp://hdl.handle.net/11693/33633
dc.descriptionCataloged from PDF version of article.en_US
dc.descriptionThesis (M.S.): Bilkent University, Department of Molecular Biology and Genetics, İhsan Doğramacı Bilkent University, 2017.en_US
dc.descriptionIncludes bibliographical references (leaves 76-84).en_US
dc.description.abstractMost of the breast cancer incidences all over the world fall into Estrogen Receptor alpha (ERα)-positive breast cancer subtype, which are treated with endocrine therapy. Tamoxifen, a selective ER modulator drug, is the most prescribed endocrine therapy option for the patients, providing a decreased mortality rate. Although patients respond to tamoxifen well initially they may lose their sensitivity to tamoxifen and develop resistance which is a major obstacle when tackling ERα-positive breast cancer. Global transcriptome analyses performed in recent years demonstrated that most parts of the genomic DNA that are transcribed into RNA are not further translated into proteins. RNA molecules that are not converted into proteins and are therefore called non-coding RNAs (ncRNA) were found to be involved in cellular processes like sequence-specific chromosome modifications, gene silencing and regulation of protein signaling pathways. While the roles of protein and microRNA (miRNA) regulators in the tamoxifen resistance have been identified, the roles of long non-coding RNAs in tamoxifen resistance are still elusive. To elucidate the impact of the long non-coding transcripts in tamoxifen resistance, I have developed acquired tamoxifen resistant ERα-positive cell line models and examined alterations in their transcriptome with respect to long non-coding RNA expression. The results of whole genome RNA-Seq analysis showed that 330 long non-coding transcripts were differentially expressed in the tamoxifen resistant cell line compared to its parental counterpart. I filtered-out ncRNAs according to criteria based on fold change, cancer association, and being a validated lncRNA, and I ended up with two candidate lncRNAs. Here, I continued with the upregulated candidate lncRNA and confirmed its elevated expression by qRT-PCR in both of the in vitro acquired tamoxifen resistant cell line models I used. Moreover, I showed that knockdown of the candidate lncRNA using antisense oligonucleotide (ASO) re-sensitizes resistant cells to tamoxifen. This sensitization effect of candidate lncRNA was achieved via induction of autophagy shown by increased LC3 II/LC3 I ratio followed by apoptosis evidenced by cleaved Caspase 7 when the lncRNA was targeted. Finally, analysis of tamoxifen-treated, ERα-positive breast cancer patient data sets suggested that higher expression of the candidate lncRNA was associated with poor overall, relapse-free and disease-free survival of the patients. Overall, in this thesis, I identified a novel lncRNA regulator of tamoxifen resistance and a potential biomarker of therapy response.en_US
dc.description.statementofresponsibilityby Hilal Bal.en_US
dc.format.extentviii, 84 leaves : charts (some color) ; 30 cmen_US
dc.language.isoEnglishen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectTamoxifenen_US
dc.subjectDrug resistanceen_US
dc.subjectlncRNAen_US
dc.subjectER positiveen_US
dc.subjectBreast canceren_US
dc.titleIdentification of long non-coding RNAs overcoming tamoxifen resistance in estrogen receptor alpha positive breast canceren_US
dc.title.alternativeÖstrojen reseptörü alfa pozitif meme kanserinde tamoksifen direncini kıran uzun kodlanmayan RNA’ların belirlenmesien_US
dc.typeThesisen_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.publisherBilkent Universityen_US
dc.description.degreeM.S.en_US
dc.identifier.itemidB156446
dc.embargo.release2019-09-12


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