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dc.contributor.advisor Pukrop, Tobias Prof. Dr.
dc.contributor.author Schubert, Antonia
dc.date.accessioned 2016-10-26T11:31:25Z
dc.date.available 2016-11-29T23:50:06Z
dc.date.issued 2016-10-26
dc.identifier.uri http://hdl.handle.net/11858/00-1735-0000-002B-7C4D-A
dc.language.iso deu de
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc 610 de
dc.title Wnt-Signalwegsanalysen während der Metastasierung von Mamma-Karzinomen de
dc.type doctoralThesis de
dc.title.translated Wnt-Signaling in Breast Cancer and Tumor Progression de
dc.contributor.referee Bastians, Holger Prof. Dr.
dc.date.examination 2016-11-21
dc.description.abstracteng Wnt signaling plays a crucial role in developmental processes and diseases such as cancer. We recently revealed activation of β-Catenin independent Wnt signaling in cerebral metastases of breast cancer patients (Klemm F et al., Carcinogenesis 2011) In particular, Wnt5a/b, ROR1-2 as well as c-jun were highly expressed in cerebral metastases samples. We also demonstrated prognostic relevance of a β-Catenin independent Wnt signaling score including DVL3 in liver metastases (Bleckmann A et al., Clin Exp Metastasis 2016). DVL has been described as a key player in both β-Catenin dependent and independent Wnt pathways. In humans three different subtypes have been identified containing three highly conserved domains: DIX (necessary for β-Catenin signaling), PDZ and DEP (conducting PCP and Wnt/Ca2+ signals). It was still largely unclear how DVL discriminates between these sub-pathways and how this influences breast cancer invasion and metastasis. The goal of this work was therefore to find out more about the role of Wnt signaling in breast cancer and tumor progression. Breast cancer cell lines as well as in the benign cell line hTERT-HME were characterized regarding the amount and localization of various Wnt markers. After overexpression of ROR2 a morphological alteration of MCF-7 and increased invasiveness without effects on proliferation was observed. Signaling analysis demonstrated no effect on the levels and location of β-Catenin. However, DVL3 was massively stabilized. The following overexpression of DVL3 wild type (wt) and various DVL3 knock-out constructs revealed DVL3’s pro-invasive potential in the luminal A cell line MCF7 independent of the DIX reliant formation of dynamic aggregates. Interestingly, the overexpression of DVL3 (wt) even inhibited migration. DVL3 deltaDIX, though reducing the activation of β-Catenin, was still pro-invasive. Overexpression of DVL3 deltaDEP did not increase invasiveness indicating a potential therapeutic target. Immunohistochemical stainings of cerebral metastases samples (N=31) were analyzed regarding their amount and the localization of DVL3. Nearly all metastases expressed DVL3 (30/31) but expression patterns varied. It could be found partly only in the cytoplasm and partly in both cytoplasm and nucleus. The results of this work demonstrate the complexity of the Wnt dependent pathways. Furthermore, they underline the significance of β-Catenin independent Wnt signaling for breast cancer progression. In particular ROR2 and the DEP domain of DVL3 are able to enhance the invasion of a low invasive breast cancer cell line independent of β-Catenin and DVL3 aggregates. de
dc.contributor.coReferee Mausberg, Rainer Prof. Dr.
dc.subject.eng Wnt de
dc.subject.eng Breast Cancer de
dc.subject.eng Tumor Progression de
dc.subject.eng EMT de
dc.subject.eng Dishevelled de
dc.subject.eng ROR1/2 de
dc.subject.eng Metastasis de
dc.identifier.urn urn:nbn:de:gbv:7-11858/00-1735-0000-002B-7C4D-A-1
dc.affiliation.institute Medizinische Fakultät de
dc.subject.gokfull Innere Medizin - Allgemein- und Gesamtdarstellungen (PPN619875747) de
dc.description.embargoed 2016-11-28
dc.identifier.ppn 871256355

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