Insulin-like growth factor binding protein-4 and -5 modulate ligand-dependent estrogen receptor-α activation in breast cancer cells in an IGF-independent manner.

Abstract

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.

• Authors: Alexander Hermani, Ashish Shukla, Senad Medunjanin, Haim Werner, Doris Mayer
• Journal: Cellular signalling (Cell Signal) Vol. 25 Issue 6 Pg. 1395-402 (Jun 2013) ISSN: 1873-3913 [Electronic] England
• PMID: 23499909 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Estrogen Receptor alpha
• Insulin-Like Growth Factor Binding Protein 4
• Insulin-Like Growth Factor Binding Protein 5
• RNA, Messenger
• RNA, Small Interfering
• Recombinant Proteins
• Estradiol
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• glycogen synthase kinase 3 alpha

Topics

• Breast Neoplasms (metabolism, pathology)
• Cell Proliferation (drug effects)
• Estradiol (pharmacology)
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Glycogen Synthase Kinase 3 (metabolism)
• Humans
• Insulin-Like Growth Factor Binding Protein 4 (genetics, metabolism)
• Insulin-Like Growth Factor Binding Protein 5 (genetics, metabolism)
• Insulin-Like Growth Factor I (metabolism)
• MCF-7 Cells
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA Interference
• RNA, Messenger (metabolism)
• RNA, Small Interfering (metabolism)
• Receptor, IGF Type 1 (antagonists & inhibitors, genetics, metabolism)
• Recombinant Proteins (biosynthesis, genetics, pharmacology)
• Signal Transduction (drug effects)
• Transcription, Genetic