title: IGF-IR cooperates with ERα to inhibit breast cancer cell aggressiveness by regulating the expression and localisation of ECM molecules.
abstract: IGF-IR is highly associated with the behaviour of breast cancer cells. In ERα-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 ERα-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 ERα-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-ERα signaling pathway seems to be essential, highlights IGF-IR as a major molecular target for novel therapeutic strategies.
authors.affiliation: Biochemistry, Biochemical Analysis &Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.|Biotech Research and Innovation Center, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Afratis
authors.affiliation: Biochemistry, Biochemical Analysis &Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Bouris
authors.affiliation: Biochemistry, Biochemical Analysis &Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.
authors.forename: Spyros S
authors.initials: SS
authors.lastname: Skandalis
authors.affiliation: Biotech Research and Innovation Center, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Hinke A
authors.initials: HA
authors.lastname: Multhaupt
authors.affiliation: Biotech Research and Innovation Center, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: John R
authors.initials: JR
authors.lastname: Couchman
authors.affiliation: Biochemistry, Biochemical Analysis &Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.
authors.forename: Achilleas D
authors.initials: AD
authors.lastname: Theocharis
authors.affiliation: Biochemistry, Biochemical Analysis &Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.
authors.forename: Nikos K
authors.initials: NK
authors.lastname: Karamanos
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D047628:Estrogen Receptor alpha; D017526:Receptor, IGF Type 1