Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/srep40138
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Funding
- European Union (European Social Fund - ESF)
- Greek national funds through the Operational Program Education and Lifelong Learning of the National Strategic Reference Framework (NSRF) - Research Funding Program: Thales
- GLYCANC research program in the context of MSCA-RISE: Marie Skodowska-Curie Research and Innovation Staff Exchange (RISE) - EU [645756]
- Hellenic State Scholarship Foundation
- EMBO short-term fellowship
- Marie Curie Actions (MSCA) [645756] Funding Source: Marie Curie Actions (MSCA)
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IGF-IR is highly associated with the behaviour of breast cancer cells. In ER alpha-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 ER alpha-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 ER alpha-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-ER alpha signaling pathway seems to be essential, highlights IGF-IR as a major molecular target for novel therapeutic strategies.
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