Tamoxifen interferes with the insulin-like growth factor I receptor (IGF-IR) signaling pathway in breast cancer cells.
The insulin-like growth factor I receptor (IGF-IR) is involved in the control of breast cancer cell growth. The cytostatic activity of tamoxifen (Tam), a nonsteroidal antiestrogen, is partially mediated through interference with IGF-I-R-dependent proliferation, yet the effects of Tam on IGF-IR intracellular signaling have never been elucidated. Consequently, we investigated how Tam modifies the IGF-IR signaling pathway in estrogen receptor-positive MCF-7 breast cancer cells and in MCF-7-derived clones overexpressing either the IGF-IR (MCF-7/IGF-IR cells) or its major substrate, IRS-1 (MCF-7/IRS-1 cells). MCF-7/IGF-IR and MCF-7/IRS-1 cells exhibit greatly reduced estrogen growth requirements but retain estrogen receptors and express sensitivity to antiestrogens comparable to that in the parental cells. In all tested cell lines, regardless of the amplification of IGF signaling, a 4-day treatment with 10 nM Tam produced a similar cytostatic effect. In MCF-7 and MCF-7/IGF-IR cells, growth inhibition by Tam was associated with the reduced tyrosine phosphorylation of the IGF-IR in the presence of IGF-I; however, the basal level of the IGF-IR remained unaffected. Moreover, Tam inhibited both basal and IGF-I-induced tyrosine phosphorylation of IRS-1, which was accompanied by down-regulation of IRS-1-associated phosphatidylinositol 3'-kinase activity and reduced IRS-1/growth factor receptor-bound protein 2 (GRB2) binding. In contrast, under the same treatment, tyrosine phosphorylation of Src-homology/collagen proteins (SHC; another substrate of the IGF-IR) and SHC/GRB2 binding were elevated. The protein levels of the IGF-IR and IRS-1 were not modified by Tam, whereas SHC protein expression was either not affected or moderately decreased by the treatment. In summary, this work provides the first evidence that in MCF-7 cells, cytostatic effects of Tam are associated with the modulation of IGF-IR signaling, specifically with: (a) down-regulation of IGF-I-induced tyrosine phosphorylation of the IGF-IR; (b) inhibition of IRS-1/phosphatidylinositol 3'-kinase signaling; and (c) up-regulation of SHC tyrosine phosphorylation and increased SHC/GRB2 binding. It is hypothesized that dephosphorylation of IRS-1 could be a major contributing factor in Tam cytostatic activity.
Guvakova
M A
MA
Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Surmacz
E
E
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000502:physiology; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D011506:Proteins; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013629:Tamoxifen; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1