Phd Degree / Doktora

Permanent URI for this collectionhttps://hdl.handle.net/11147/2869

Browse

Filters

2020 - 20223

Settings

Department: search.filters.department.Thesis (Doctoral)--İzmir Institute of Technology, Molecular Biology and GeneticsSubject: search.filters.subject.Breast cancer

Search Results

Now showing 1 - 3 of 3
  • Doctoral Thesis
    Investigating Molecular Mechanisms Underlying Resistance To Notch Inhibitors in Breast and Ovarian Cancer
    (2022) Telli, Kübra; Yalçın Özuysal, Özden; Yalçın Özuysal, Özden; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of Technology
    Breast and ovarian cancers remain highly malignant among women with more than 11% overall of incidence rates worldwide. Traditional treatment strategies including chemotherapy, radiotherapy and hormone therapies continues to be successful yet for the long-term, cancer recurrence and drug resistance remains to be the main issue. In addition to the altering common cell fate regulations, cancer cells modify signaling pathways to overcome cytotoxicity. Notch signalling pathway is a conserved ligand-receptor pathway that necessarily plays role in survival homeostasis, yet it is dysregulated in various cancers. Currently, novel treatment strategies are targeting this pathway through Gamma Secretase Inhibitors (GSI) DAPT, R04929097 and MK0752 that are use both as a single agent and in combinations with Docetaxel or Cisplatin. The clinical success of these inhibitors requires further examination of potential intrinsic or acquired resistance profiles. In this study, we generated breast cancer cells (MDA-MB-231 and MCF-7) resistant to DAPT or R04929097 and ovarian cancer cells (IGROV-1, BG-1, SKOV-3 and A2780) resistant to MK0752 by gradual treatments of increasing doses based on drugs’ IC50 values. Morphological changes, growth rates, migration alterations, mRNA expressions of Notch pathway components and epithelial mesenchymal transition markers, 3D setups for acidosis responses and protein expressions for c-myc and oxidative stress response markers were analyzed. Furthermore, proteomic analysis was carried out with the ovarian cancer cell line IGROV-1. The response of the cells to different drug treatments and dysregulated protein families exposed in resistance mechanisms behind DAPT, R04929097 and MK0752 for both breast and ovarian cancer cells are reported. Overall, this study reveals possible resistance mechanisms against GSIs and emphasizes potential targets through well-known hallmarks of cancer drug resistance.
  • Doctoral Thesis
    Detection of the Metastatic Potential of Breast Cancer Cell Lines To Specific Target Tissues
    (01. Izmir Institute of Technology, 2021) Fıratlıgil Yıldırır, Burcu; Yalçın Özuysal, Özden; Yalçın Özuysal, Özden; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of Technology
    Breast cancer is one of the most frequently diagnosed cancer types and the second leading cause of cancer-associated deaths in women. Breast cancer begins as a local disease which can then metastasize to distant sites specifically to bone, lung and liver. The increasing rate of the metastasis-related deaths asserts the need to develop in vitro diagnostic strategies representing in vivo properties better. In this study, two different lab-on-a-chip (LOC) platforms, IC- and EX-chips, were used to detect the invasion and extravasation potentials, respectively, of breast cancer cells to 3D in vitro generated bone, lung, liver and breast microenvironments. The metastatic MDAMB231, but not non-metastatic MCF7 breast cancer cells showed higher invasion and extravasation potentials towards lung and liver microenvironments than breast microenvironment. Lung-specific but not bone-specific metastatic subclonal cells invaded significantly towards lung microenvironment. On the other hand, an intensive invasion was observed in bone-specific but not lung-specific metastatic subclonal cells towards bone microenvironment demonstrating different in vivo metastatic behaviors of breast cancer cells. Overall, the tissue-specific invasion and extravasation capacities of breast cancer cells were demonstrated with IC- and EX-chips where the physiologically more relevant bone, lung, liver and breast homing target sites were generated by a specific emphasis on ECM components, stromal cells and secreted factors. This study is important in providing a basis for the development of diagnostic tools and precision therapeutics for breast cancer metastasis.
  • Doctoral Thesis
    Investigating the Role of Connexin 32 in Breast Cancer
    (Izmir Institute of Technology, 2020) Meşe Özçivici, Gülistan; Uğur, Deniz; Meşe Özçivici, Gülistan; 04.03. Department of Molecular Biology and Genetics; 01. Izmir Institute of Technology; 04. Faculty of Science
    Connexins (Cx) are primary components of gap junctions, selectively allowing molecules to be exchanged between adjacent cells. Along with their channel forming functions, connexins play variety of roles in different stages in tumorigenesis, both dependent and independent of gap junctions in connexin and cancer dependent manner. Cytoplasmic accumulation of Cx32 was shown in some breast cancers; and compared to the primary tumors Cx32 is further upregulated in metastasis. However, the complete picture for the role of Cx32 in breast cancer remains to be elusive. Through overexpressing Cx32, its functions in breast cancer cells were investigated in Hs578T and MCF7 breast cancer cells. Cx32 overexpression increased cellular proliferation with significant increase in S phase in Hs578T cells with no significant change on MCF7 cells. Cx32 overexpression did not induce hemichannel activity in neither cell; it reduced gap junctional functions in Hs578T cells. Cx32 in both cells localized in cytoplasm did not form intercellular plaques, and decreased Cx43 expression. Cx32 overexpression reduced the migration and invasion capacity in both cells and in Hs578T cells showed reduction of mesenchymal and increase of epithelial marker expressions. In conclusion, Cx32 increases proliferation and decreases communication in Hs578T cells while not affecting MCF7 cells. It decreases aggressiveness and metastatic potential for both cell lines. Due to changes in gap junctional functions, Cx32 might be acting in relation to GJIC in Hs578T cells and outside of it in MCF7 cells. All in all, presence of Cx32 made Hs578T cells act similar to endogenously Cx32 expressing MCF7 cells.