الفهرس 
AbstractOnly 14 pages are availabe for public view
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Abstract
Cancer cell metastasis is one of the most critical steps in tumor development and is responsible for more than 80% of cancer related deaths. Among the molecules involved in promoting cancer metastasis is the cell adhesion molecule CD44, whose role in promoting cancer cell motility and metastasis is well known. Despite this knowledge, the molecular mechanism through which CD44 promotes tumor development and cell metastasis is still unclear. In this thesis we identified the anti-apoptotic protein Survivin (SVV) as a novel downstream target of CD44 determining a new role of CD44 in promoting cancer cell survival through induction of SVV and identifying a functional role of SVV in breast cancer metastasis. We also analyzed the signal transduction pathway linking CD44 activation and SVV expression, proposing the transcription factor E2F1 as a potential downstream target of HA/CD44 signaling implicated in SVV transcription. Second, based on the above mentioned data, we used a pharmaceutical approach to control the metastatic capability of CD44 thereby proposing a potential way to induce cancer cell death. In order to do this we utilized chemopreventive phytochemicals naturally present in fruits and vegetables (Genistein, Indol-3-Carbinol, C-phycocyanin, Resveratrol, Quercetin and Curcumin) singly and in combination to determine their ability to inhibit CD44-dependent cell migratory ability and induction of cell death. In addition, we studied the mechanisms of action of these molecules to inhibit breast cancer cell growth, metastasis, and the induction of cell death via targeting several subcellular pathways. Finally, we present preliminary studies demonstrating CD146 (another member of cell adhesion molecules family) as a downstream target of CD44, regulating its neovascularization and cancer cell transmigration of blood vessels promoting functions.