Abstract:

IGF-IR is highly associated with the behaviour of breast cancer cells. In ERalpha-positive breast cancer, IGF-IR is present at high levels. In clinical practice, prolonged treatment with anti-estrogen agents results in resistance to the therapy with activation of alternative signaling pathways. Receptor Tyrosine Kinases, and especially IGF-IR, have crucial roles in these processes. Here, we report a nodal role of IGF-IR in the regulation of ERalpha-positive breast cancer cell aggressiveness and the regulation of expression levels of several extracellular matrix molecules. In particular, activation of IGF-IR, but not EGFR, in MCF-7 breast cancer cells results in the reduction of specific matrix metalloproteinases and their inhibitors. In contrast, IGF-IR inhibition leads to the depletion by endocytosis of syndecan-4. Global important changes in cell adhesion receptors, which include integrins and syndecan-4 triggered by IGF-IR inhibition, regulate adhesion and invasion. Cell function assays that were performed in MCF-7 cells as well as their ERalpha-suppressed counterparts indicate that ER status is a major determinant of IGF-IR regulatory role on cell adhesion and invasion. The strong inhibitory role of IGF-IR on breast cancer cells aggressiveness for which E2-ERalpha signaling pathway seems to be essential, highlights IGF-IR as a major molecular target for novel therapeutic strategies.

Notes:

Afratis, Nikolaos ABouris, PanagiotisSkandalis, Spyros SMulthaupt, Hinke ACouchman, John RTheocharis, Achilleas DKaramanos, Nikos KengResearch Support, Non-U.S. Gov'tEngland2017/01/13Sci Rep. 2017 Jan 12;7:40138. doi: 10.1038/srep40138.