Molecular mechanisms regulating epithelial-to-mesenchymal transition and therapy sensitivity in breast cancer and glioblastoma

This thesis is aimed at identifying novel therapeutic targets for breast cancer and aggressive brain tumors in preclinical models. Metastatic disease is the main cause of cancer-related deaths, including breast cancer. Poor prognosis is related to limited therapeutic effect as a result of treatment resistance to current therapies, such as chemotherapy, radiotherapy and hormone-based therapies.  Novel treatments that prevent resistance or metastasis are highly needed. The cellular process of epithelial-to-mesenchymal transition (EMT) known to stimulate the afore mentioned malignant properties may provide novel targets for therapy. We found the Notch3 signaling pathway to play an important role in maintaining an epithelial phenotype in breast cancer and suppress tumorigenesis and metastases. Underlying molecular mechanisms were identified that proves additional possible targets for therapy. Furthermore, the tumor promoting properties of the cell membrane localized cell adhesion protein CD146 was investigated in both breast cancer and brain tumor cell culture models. In breast cancer, CD146 appeared to induce EMT and enhance chemotherapy (cisplatin) and hormone therapy (tamoxifen) resistance sensitivity. In glioblastoma, the most aggressive and lethal brain tumor in adults, CD146 promoted malignant behavior of tumor cells, including cancer stem cell properties, invasive potential and radiotherapy resistance, in glioblastoma spheroid models. These findings indicate that CD146 could be a promising target in both breast cancer and glioblastoma. In summary, the development of targeted therapy against these identified EMT mechanisms and related malignant tumor properties may contribute to a better prognosis for these cancer patients.

Dissertation: http://hdl.handle.net/11370/82354e58-88c8-431e-acae-5fd0a840b767