Ph.D. Theses
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Browsing Ph.D. Theses by Subject "Breast -- Cancer."
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Item SIK2 functions as a novel tumor suppressor in the breast tumorigenesis(Thesis (Ph.D.)-Bogazici University. Institute for Graduate Studies in Science and Engineering, 2015., 2015.) Zohrap, Neslihan.; Buğra, Kuyaş.Breast cancer has highly malignant phenotype and is the leading cause of cancer death in women. The heterogenous character of the disease points to the importance of novel target identification for the development of effective therapies. Perturbation in receptor tyrosine kinase (RTK) pathway elements are frequently implicated in cancer. Our group has shown that SIK2 functions downstream of FGFR signaling, and control proliferation and survival. Given the importance of strict control of RTK pathways in cancer, in this study, we aimed to investigate the potential role of SIK2 in the development of tumorigenicity. In this context, screening of a cDNA array indicated downregulation of SIK2 transcript levels in breast cancer. A query into Oncomine database validated frequent reduction of SIK2 expression and loss of copy number in dataset covering a large breast cancer patient cohort. Immunohistochemical studies localized SIK2 in ductal epithelia of breast tissue and showed that SIK2 levels decline in all triple negative breast cancer (TNBC) cases and in half of the hormone positive tumors. These studies also indicated that inverse correlation exists between SIK2 and Ki67 indicating a negative effect of SIK2 on mitotic potential. Reduced SIK2 expression in breast tumor cell lines was also evident. Modulation of SIK2 expression in MDA-MB-231 and MCF12A breast lines suggested that SIK2 negatively regulate proliferation and survival by preventing ERK and Akt activation. In this context, its kinase activity appears to be required. In vitro studies also indicate that SIK2 may also be involved in the regulation of cellular adhesion and invasion. Xenografting experiments provided strong evidence that SIK2 hampers tumor growth through downregulation of proliferation and survival. In the light of these findings, we propose SIK2 as a novel tumor suppressor, loss of its expression/activity promote breast tumorigenesis.Item The effect of nNav1.5 gene expression in breast cancer metastasis(Thesis (Ph.D.)-Bogazici University. Institute for Graduate Studies in Science and Engineering, 2006., 2006.) Yamacı, Rezan Fahrioğlu.; Battaloğlu, Esra.Breast cancer is the most common cancer among women. Its metastasis is lethal that can not be detected at microscopic levels using current techniques. Thus, there is need for reliable early metastasis markers. Neonatal Nav1.5 (nNav1.5) is a voltage-gated sodium channel (VGSC) and one of the potential early markers for breast cancer metastasis. In this study, we determined that nNav1.5 expression was in parallel with breast cancer metastasis and estrogen receptor (ER) expression in a group of patients. To provide data for future drug development, we analyzed the expression pattern of nNav1.5 protein in normal human tissues. The protein was not expressed in skeletal and heart muscle, brain, small intestine, colon, stomach, esophagus, urinary bladder and prostate but expressed in breast at basal level. We also investigated the distribution of VGSC in these non-excitable human tissues. Except urinary bladder, VGSC protein was determined mostly in secretory cells in all of the tissues above that may indicate a role in secretion. Upon identification of VGSC upregulation in tumor regions of different cancers including, colon, stomach, urinary bladder, kidney and lung it is possible that VGSC expression could be a widespread mechanism in cancer metastasis. Within the scope of this thesis, we also investigated the possible role of estrogen on nNav1.5 upregulation and activity in metastatic breast cancer. Estrogen had no effect on proliferation of cells but slightly increased motility through nNav1.5 in highly metastatic cells that express the protein. In weakly metastatic cells that do not posses nNav1.5, estrogen decreased motility slightly. The quantity of nNav1.5 protein was not affected by estrogen but functionally available form on the plasma membrane was increased only in the highly metastatic cells. These results may suggest that estrogen increases motility capacity of breast cancer cells by regulating nNav1.5 activity.