title: IGF-I/EGF and E2 signaling crosstalk through IGF-IR conduit point affects breast cancer cell adhesion.
abstract: Epidermal growth factor (EGF)/insulin like growth factor-I (IGF-I) and Estradiol (E2) can regulate biological functions of hormone-dependent tumor cells. Fibronectin (FN) is a large glycoprotein abundantly expressed in breast cancer extracellular matrices (ECMs) postulated to be a marker of aggressiveness during cancer pathogenesis. In this study we demonstrate that IGF-I/EGF as well E2 strongly increase the adhesion of the MCF-7 breast cancer cells onto FN. Moreover, IGF-IR is necessary for the IGF-I-/EGF- and E2-induced cell adhesion. Erk1/2 inhibition abolished the IGF-I-/EGF-/E2-induced MCF-7 cell adhesion, suggesting that this regulation of cell adhesion is perpetrated through Erk1/2 downstream signaling. Erk1/2 signaling was shown to modulate IGF-IR status as its' inhibition attenuates both IGF-IR expression and activation. Notably, EGF and E2 enhanced the mRNA as well as protein expression of IGF-IR in MCF-7 cells. Confocal microscopy demonstrated that treatment of MCF-7 cells with IGF-I or EGF induced actin reorganization, which was attenuated with Erk1/2 inhibition. Interestingly, IGF-I treatment induced a co-localization of IGF-IR and FAK, which was evident mostly at the cell membranes of MCF-7 cells. In summary, IGF-IR was shown to be a convergence point for the IGF-/EGF- and E2-dependent MCF-7 cell adhesion onto FN.
authors.affiliation: Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Kallirroi
authors.initials: K
authors.lastname: Voudouri
authors.affiliation: Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Dragana
authors.initials: D
authors.lastname: Nikitovic
authors.affiliation: Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Berdiaki
authors.affiliation: Laboratory of Cell Proliferation and Ageing, Institute of Biology, National Center of Scientific Research "Demokritos", Athens, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kletsas
authors.affiliation: Biochemistry, Biochemical Analysis and Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece.
authors.forename: Nikos K
authors.initials: NK
authors.lastname: Karamanos
authors.affiliation: Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece. Electronic address: tzanakak@med.uoc.gr.
authors.forename: George N
authors.initials: GN
authors.lastname: Tzanakakis
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000502:physiology*; D004958:Estradiol / Q000502:physiology*; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D021381:Protein Transport; D020239:Receptor Cross-Talk; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004958:Estradiol; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
keywords: Adhesion; Breast cancer; E2; EGF; IGF-I; IGF-IR