Δυναμική αλληλεπίδραση μεταξύ της σηματοδότησης του ERα, των αυξητικών παραγόντων και των μορίων του εξωκυττάριου χώρου στην επιθετική συμπεριφορά των καρκινικών κυττάρων μαστού

The aggressive behavior and the mesenchymal phenotype are two critical cancer cell properties which are closely associated with tumor development, progression and metastasis. The regulation of these properties in breast cancer is significantly mediated by several signaling molecules, including estrogen receptors and receptors tyrosine kinases. Some ECM molecules, such as proteoglycans and proteolytic enzymes, are also crucial mediators of the above mentioned cellular properties in cancer. Our findings revealed specific molecules and possible mechanisms of action which actively mediate the regulation of aggressiveness and the mesenchymal morphology of breast cancer cells. More specifically, we demonstrated that the silencing of ERα induces EMT and promotes the aggressive behavior of MCF-7 breast cancer cells. In addition, the suppression of ERα activates cell signaling which is responsible for the mediation of aggressiveness, as well as enhances the expression and the activity of a plethora of critical proteolytic molecules. On the other hand, we demonstrated that IGF-IR promotes the mild behavior of breast cancer cells through an ERα-dependent manner, and the same time regulates the expression of specific MMPs/TIMPs. Furthermore, we report that the inhibition of the RTKs AXL and PDGFRβ causes a partial MET and strongly suppresses the high aggressive behavior of MDA-ΜΒ-231 breast cancer cells, thus highlighting the crucial role of these RTKs on the maintenance of mesenchymal phenotype and the aggressiveness in breast cancer. Moreover, the impact of AXL and PDGFRβ on cell signaling, while the crosstalk between the pathways of the RTKs with TGFβ signaling axis was also revealed. Finally, we demonstrated that serglycin mediates the induction of aggressiveness in breast cancer, through the regulation of crucial signaling pathways, including the IL-8/CXCR-2 pathway. Last but not least, it was shown that the overexpression of serglycin enhances the biosynthesis and the activity of the proteolytic network molecules, while it partly induces EMT and confers chemoresistance against commercially available anticancer drugs. Collectively, our data define the decisive regulatory role of all the above mentioned effectors of the aggressive behavior and the mesenchymal phenotype of breast cancer cells, as well as reveal possible mechanisms of action, thus highlighting the complexity for the regulation of these cell properties in breast cancer.