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

Abstract

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 oligodeoxynucleotides (ASODNs) directed to ErbB-2 mRNA with ASODNs directed to the insulin-like growth factor-I receptor (IGF-IR) were used to study the eect of the simultaneous block of these receptors on the MPAinduced proliferation of epithelial cells from the progestin-dependent C4HD line. Neither synergistic nor additive eects 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 aect 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 ®rst 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. Oncogene (2001) 20, 34 ± 47.

Co-Targeting Insulin-Like Growth Factor I Receptor and HER2: Dramatic Effects of HER2 Inhibitors on Nonoverexpressing Breast Cancer

“…In one model, the mitogenic effect of neuregulin was inhibited by an antisense oligodeoxynucleotide to the IGFIR (21). This model also showed IGFIR/HER2 cross-talk and physical association (22). IGFIR and HER2 physically associated as shown by coimmunoprecipitation and confocal microscopy.…”

Heregulin Induces Transcriptional Activation of the Progesterone Receptor by a Mechanism That Requires Functional ErbB-2 and Mitogen-Activated Protein Kinase Activation in Breast Cancer Cells

“…We have recently proved the presence of interactions between progestins and HRG signaling pathways in an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in female BALB/c mice (4,5). Our previous studies have demonstrated the capacity of progestins to activate ErbB-2 and ErbB-3 and to induce HRG synthesis (4,5).…”

“…Convergence between steroid hormones and RTK signaling pathways has a bidirectional nature in which steroid hormones activate either RTKs or their downstream signaling pathways (4,5,9,39,45,58) and where, conversely, RTK ligands are able to modulate steroid receptor transcriptional activity (32,33,51,60,64). Steroid-independent activation of estrogen receptor (ER) by EGF and IGF-I, ligands of the type I and II RTKs, respectively, has long been described (11,31,32,33).…”

Direct Involvement of Breast Tumor Fibroblasts in the Modulation of Tamoxifen Sensitivity

“…In homotypic EIII8-TAM R and heterotypic EIII8-TAM R fibroblast cultures, an overall increase in levels of total and activated EGFR and IGF-1R that is independent of stroma along with hyperactivation of MAPK, Akt, and phosphorylation of ER-␣ are observed. It is possible that direct and indirect interactions between IGF and EGF pathways demonstrated in several cell types including breast cancer cells 53,54 might play an important role in the intrinsic tamoxifen resistance of EIII8-TAM R cells.…”