Identifying and targeting coding/non-coding molecular switches regulating drug resistance and metastasis in breast cancer

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buir.advisorŞahin, Özgür
dc.contributor.authorRaza, Umar
dc.date.accessioned2017-09-25T08:43:17Z
dc.date.available2017-09-25T08:43:17Z
dc.date.copyright2017-09
dc.date.issued2017-09
dc.date.submitted2017-09-22
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.descriptionCataloged from PDF version of article.en_US
dc.descriptionThesis (Ph.D.): Bilkent University, Department of Molecular Biology and Genetics, İhsan Doğramacı Bilkent University, 2017.en_US
dc.descriptionIncludes bibliographical references (leaves 136-152).en_US
dc.description.abstractBreast cancer is the second most common cancer and the leading cause of cancer associated deaths in women worldwide. Despite the availability of large number and various types of therapy agents which are effective in limiting tumor burden at initial stages, cancer cells still manage to resist to therapy treatment and exhibit re-growth of existing tumor or metastasize to distant organs. Therefore, there is a dire need to identify underlying molecular mechanisms to enhance therapy response and to block metastasis. In addition to coding genome, non-coding RNAs have also play active role in controlling proliferation, apoptosis, invasion and drug resistance in cancer. Therefore, I aimed to identify novel coding/non-coding molecular switches regulating drug resistance and metastasis in breast cancer. In the first part of this dissertation, I identified miR-644a as a novel tumor suppressor inhibiting both cell survival and epithelial mesenchymal transition (EMT) whereby acting as pleiotropic therapy-sensitizer in breast cancer. Both miR-644a expression and its gene signature are associated with tumor progression and distant metastasis-free survival. Mechanistically, miR-644a directly targets the transcriptional co-repressor C-terminal binding protein 1 (CTBP1) whose knock-outs by the CRISPR-Cas9 system inhibit tumor growth, metastasis, and drug resistance, mimicking the phenotypes induced by miR-644a. Furthermore, miR-644a/CTBP1-mediated upregulation of wild type- or mutant-p53 acts as a ‘molecular switch’ between G1-arrest and apoptosis by inducing p21 or Noxa, respectively. Interestingly, an increase in mutant-p53 by either overexpression of miR- 644a or downregulation of CTBP1 was enough to shift the balance between cell cycle arrest and apoptosis in favor of apoptosis through the upregulation of Noxa. Notably, p53-mutant patients, but not p53-wild type ones, with high CTBP1 level have a shorter survival suggesting that CTBP1 could be a potential prognostic factor for breast cancer patients with p53 mutations. Overall, modulation of the miR-644a/CTBP1/p53 axis may represent a new strategy for overcoming both therapy resistance and metastasis. In the second part of this dissertation, I performed whole transcriptome sequencing with downstream pathway analysis in the chemoresistant triple negative breast cancer (TNBC) tumors we developed in vivo. This suggested a potential role of integrins and hypoxia in chemoresistance. Mechanistically, we showed that our candidate gene is hypoxia-induced and is overexpressed in resistant tumors, and activates integrin subunit alpha 5 (ITGA5). In the meantime, hypoxia-mediated downregulation of a miRNA targeting our candidate gene, leads to further activation of the ITGA5. This culminates in the activation of FAK/Src signaling thereby mediating resistance. Importantly, higher expression of our candidate gene, or lower expression of miRNA was associated with poorer relapse-free survival only in chemotherapy-treated TNBC patients. Finally, inhibition of candidate gene increased the efficacy of chemotherapy in highly aggressive TNBC models in vivo providing pre-clinical evidence for testing inhibitors against our candidate gene to overcome chemoresistance in TNBC patients.en_US
dc.description.degreePh.D.en_US
dc.description.statementofresponsibilityby Umar Raza.en_US
dc.embargo.release2020-09-22
dc.format.extentxxiii, 153 leaves : charts (some color) ; 30 cmen_US
dc.identifier.itemidB156497
dc.identifier.urihttp://hdl.handle.net/11693/33726
dc.language.isoEnglishen_US
dc.publisherBilkent Universityen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectBreast canceren_US
dc.subjectChemotherapy resistanceen_US
dc.subjectEMTen_US
dc.subjectMicroRNAsen_US
dc.subjectP53 signalingen_US
dc.subjectIntegrin signalingen_US
dc.subjectHypoxiaen_US
dc.subjectCTBP1en_US
dc.subjectlysyl oxidaseen_US
dc.subjectITGA5en_US
dc.titleIdentifying and targeting coding/non-coding molecular switches regulating drug resistance and metastasis in breast canceren_US
dc.title.alternativeMeme kanserinde ilaç direnci ve metastazı düzenleyen kodlanan/kodlanmayan moleküler anahtarların tanımlanması ve hedeflenmesien_US
dc.typeThesisen_US

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