Activation of ErbB-2 via a hierarchical interaction between ErbB-2 and type I insalia-like growth factor receptor in mammary tumor cells

• Autores: Balãá, M.E.; Labriola, L.; Salatino, M.; Movsichoff, F.; Peters, G.; Charreau, E.H.; Elizalde, P.V.
• Año de publicación: 2001
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: Oncogene 2001;20(1):34-47
• Materia: ErbB receptors; Mammary tumorigenesis; Progestin; Type I insulin-like growth factor receptor; antisense oligodeoxynucleotide; gestagen; medroxyprogesterone acetate; messenger RNA; neu differentiation factor; oligomer; protein tyrosine kinase; somatomedin C receptor; animal cell; animal experiment; animal model; animal tissue; article; breast carcinogenesis; breast epithelium; breast tumor; cell proliferation; complex formation; confocal laser microscopy; controlled study; female; gene activation; mouse; nonhuman; oncogene neu; priority journal; protein localization; protein phosphorylation; protein protein interaction; signal transduction; Animals; Enzyme Activation; Epithelial Cells; Female; Macromolecular Substances; Mammary Neoplasms, Experimental; Medroxyprogesterone 17-Acetate; Mice; Mice, Inbred BALB C; Oligodeoxyribonucleotides, Antisense; Phosphorylation; Progesterone Congeners; Receptor Cross-Talk; Receptor, erbB-2; Receptor, IGF Type 1; Signal Transduction; Tumor Cells, Cultured; Tyrosine; Animalia; Mink cell focus-forming virus
• Institución: Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales

The present study focused on interactions between signaling pathways activated by progestins and by type I and II receptor tyrosine kinases (RTKs) in mammary tumors. An experimental model in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in Balb/c mice was used. MPA-stimulated proliferation, both in vivo and in vitro, of progestin-dependent tumors induced up-regulation of ErbB-2 protein levels and tyrosine phosphorylation of this receptor. Combinations of antisense oligodeoxynueleotides (ASODNs) directed to ErbB-2 mRNA with ASODNs directed to the insulin-like growth factor-I receptor (IGF-IR) were used to study the effect of the simultaneous block of these receptors on the MPA-induced proliferation of epithelial cells from the progestin-dependent C4HD line. Neither synergistic nor additive effects on the inhibition of MPA-induced proliferation of C4HD cells were observed as a result of the combination of these ASODNs. Suppression of IGF-IR expression by ASODNs resulted in complete abrogation of MPA-induced phosphorylation of ErbB-2 in C4HD cells, whereas blockage of ErbB-2 did not affect IGF-IR phosphorylation. These results show the existence of a hierarchical interaction between IGF-IR and ErbB-2, by means of which IGF-IR directs ErbB-2 phosphorylation. We demonstrated, for the first time, that this hierarchical interaction involves physical association of both receptors, resulting in the formation of a heteromeric complex. Furthermore, confocal laser microscopy experiments demonstrated that MPA was able to induce co-localization of ErbB-2 and IGF-IR. This hetero-oligomer was also found in MCF-7 human breast cancer cells in which association of IGF-IR and ErbB-2 was induced by heregulin and IGF-I.
Fil:Labriola, L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Salatino, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Movsichoff, F. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Peters, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Charreau, E.H. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Elizalde, P.V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.