title: IGF-I affects glycosaminoglycan/proteoglycan synthesis in breast cancer cells through tyrosine kinase-dependent and -independent pathways.
abstract: The insulin-like growth factor I (IGF-I) has been implicated in breast cancer development acting through insulin-like growth factor I receptor (IGF-IR), but also through estrogen receptor (ER). The effect of IGF on proteoglycan (PG) synthesis by two human breast cancer epithelial cell lines, the ER-positive MCF-7 and the ER-negative BT-20, was studied alone and in combination with genistein. Both cell lines synthesise hyaluronan (HA), matrix secreted and cell membrane-associated galactosaminoglycan containing proteoglycans (GalAGPGs) and heparan sulphate proteoglycans (HSPGs) in variable amounts. IGF-I affects the synthesis of PGs by BT-20 cells by decreasing the amounts of HA and secreted GalAGPGs and HSPGs and upregulates the expression of cell membrane-associated GalAGPGs and HSPGs. IGF-I exerts this effect on BT-20 cells acting mainly through receptors with protein tyrosine kinase activity (PTK). In contrast, IGF-I stimulates the synthesis of secreted GalAGPGs and HSPGs by MCF-7 cells, exhibiting only a slight suppression on synthesis of cell-associated GalAGPGs and HSPGs. The regulatory effect of IGF-I on PGs distribution in MCF-7 cells is mediated through a mix of pathways, which involves both receptors with PTK activity and PTK-independent signalling. It is suggested that the effects of IGF-I on the synthesis and distribution of PGs by epithelial breast cancer cells also depend on the presence or the absence of ER. The result of the IGF-I action is the balanced biosynthesis between the matrix and cell-associated PGs in both cell lines, approaching a common biosynthetic phenotype.
authors.affiliation: Section of Organic Chemistry, Biochemistry and Natural Products, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece.
authors.forename: Theoni N
authors.initials: TN
authors.lastname: Mitropoulou
authors.forename: Achilleas D
authors.initials: AD
authors.lastname: Theocharis
authors.forename: Dragana
authors.initials: D
authors.lastname: Nikitovic
authors.forename: Nikos K
authors.initials: NK
authors.lastname: Karamanos
authors.forename: George N
authors.initials: GN
authors.lastname: Tzanakakis
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane; D004338:Drug Combinations; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D019833:Genistein / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D006025:Glycosaminoglycans; D019812:Heparan Sulfate Proteoglycans; D011960:Receptors, Estrogen; D007334:Insulin-Like Growth Factor I; D006820:Hyaluronic Acid; D019833:Genistein; D011505:Protein-Tyrosine Kinases