GCRIS

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Investigating Molecular Mechanisms Underlying Resistance To Notch Inhibitors in Breast and Ovarian Cancer
(2022) Telli, Kübra; Yalçın Özuysal, Özden
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.
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
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.

Phd Degree / Doktora

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