title: Overexpression of ErbB2 receptor inhibits IGF-I-induced Shc-MAPK signaling pathway in breast cancer cells.
abstract: Overexpression of the ErbB2 receptor in one-third of human breast cancers contributes to the transformation of epithelial cells and predicts poor prognosis for breast cancer patients. We report that the overexpression of ErbB2 inhibits IGF-I-induced MAPK signaling. IGF-I-induced MAPK phosphorylation and MAPK kinase activity are reduced in ErbB2 overexpressing MCF-7/HER2-18 cells relative to control MCF-7/neo cells. In SKBR3/IGF-IR cells, reduction of ErbB2 by antisense methodology restores the IGF-I-induced MAPK activation. The inhibition of IGF-I-induced MAP kinase activation in ErbB2 overexpressing breast cancer cells is correlated with decreased IGF-I-induced Shc tyrosine-phosphorylation, leading to a decreased association of Grb2 with Shc and decreased Raf phosphorylation. However, IGF-I-induced tyrosine-phosphorylation of IGF-I receptor and IRS-I and AKT phosphorylation were unaffected by ErbB2 overexpression. Consistent with these results, we observed that the proportion of IGF-I-stimulated proliferation blocked by the MAPK inhibitor PD98059 fell from 82.6% in MCF-7/neo cells to 41.2% in MCF-7/HER2-18 cells. These data provide evidence for interplay between the IGF-IR and ErbB2 signaling pathways. They are consistent with the view that the IGF-IR mediated attenuation of trastuzumab-induced growth inhibition we recently described is dependent on IGF-I-induced PI3K signaling rather than IGF-I-induced MAPK signaling.
authors.affiliation: Division of Experimental Medicine, Department of Medicine and Department of Oncology, McGill University, Montreal, Que, Canada.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Lu
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zi
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Zhao
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D002455:Cell Division; D045744:Cell Line, Tumor; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D051380:GRB2 Adaptor Protein; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008024:Ligands; D020935:MAP Kinase Signaling System; D009841:Oligonucleotides / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation; D011233:Precipitin Tests; D011379:Prognosis; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D000068878:Trastuzumab; D014443:Tyrosine / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D005419:Flavonoids; D051380:GRB2 Adaptor Protein; D007334:Insulin-Like Growth Factor I; D008024:Ligands; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D000068878:Trastuzumab; D014443:Tyrosine; C495948:GRB2 protein, human; C528024:SHC1 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one