Insulin-like growth factor binding protein-4 and -5 modulate ligand-dependent estrogen receptor-a activation in breast cancer cells in an IGF-independent manner
Insulin-like growth factor binding proteins (IGFBPs) are modulators of numerous cellular processes including cell proliferation. Although IGFBPs classically act by sequestration of extracellular insulin-like growth factors (IGFs), thereby contributing to the fine-tuning of growth factor signals, IGF...
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| Main Authors: | , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
13 March 2013
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| In: |
Cellular signalling
Year: 2013, Volume: 25, Issue: 6, Pages: 1395-1402 |
| ISSN: | 1873-3913 |
| DOI: | 10.1016/j.cellsig.2013.02.018 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.cellsig.2013.02.018 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0898656813000661 Verlag, Table of Contents, Volltext: http://www.sciencedirect.com/science/journal/08986568/25/6 
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| Author Notes: | Alexander Hermani, Ashish Shukla, Senad Medunjanin, Haim Werner, Doris Mayer |
| Summary: | Insulin-like growth factor binding proteins (IGFBPs) are modulators of numerous cellular processes including cell proliferation. Although IGFBPs classically act by sequestration of extracellular insulin-like growth factors (IGFs), thereby contributing to the fine-tuning of growth factor signals, IGF-independent actions of IGFBPs have also been described. In the breast, growth factor signaling in association with estradiol (E2)-stimulated estrogen receptor function is organized in a complex cross-talk. The importance of phosphatidylinositol 3-kinase/protein kinase B (Akt/PKB) pathway components for the E2-induced activation of estrogen receptor-alpha (ERα) is well accepted. Here we show that in the absence of IGFs, IGFBP-4 or IGFBP-5, either overexpressed in MCF-7 breast cancer cells or added exogenously, decreased the capability of E2 to induce ERα transcriptional activity. In addition, overexpression or addition of recombinant IGFBP-4 or IGFBP-5 resulted in reduction of E2-induced phosphorylation of Akt/PKB, GSK-3α/β and ERα in MCF-7 cells. The activation of the Akt/PKB-pathway describes a non-genomic effect of E2, which did not involve activation/phosphorylation of the IGF-I receptor (IGF-IR). Furthermore, knockdown of the IGF-IR did not affect the inhibition of E2-induced ERα phosphorylation by IGFBP-4 and 5. Moreover, IGFBP-4 and IGFBP-5 strongly decreased E2-triggered growth of MCF-7 cells. Our data suggest that IGFBPs interfere with the E2-induced activation of the Akt/PKB-pathway and prevent full hormone-dependent activation of ERα and breast cancer cell growth in an IGF- and IGF-IR-independent manner. |
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| Item Description: | Gesehen am 05.01.2022 |
| Physical Description: | Online Resource |
| ISSN: | 1873-3913 |
| DOI: | 10.1016/j.cellsig.2013.02.018 |