title: The IGF pathway regulates ERα through a S6K1-dependent mechanism in breast cancer cells.
abstract: The IGF pathway stimulates malignant behavior of breast cancer cells. Herein we identify the mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) axis as a critical component of IGF and estrogen receptor (ER)α cross talk. The insulin receptor substrate (IRS) adaptor molecules function downstream of IGF-I receptor and dictate a specific biological response, in which IRS-1 drives proliferation and IRS-2 is linked to motility. Although rapamycin-induced mTOR inhibition has been shown to block IGF-induced IRS degradation, we reveal differential effects on motility (up-regulation) and proliferation (down-regulation). Because a positive correlation between IRS-1 and ERα expression is thought to play a central role in the IGF growth response, we investigated the potential role of ERα as a downstream mTOR target. Small molecule inhibition and targeted knockdown of S6K1 blocked the IGF-induced ERα(S167) phosphorylation and did not influence ligand-dependent ERα(S118) phosphorylation. Inhibition of S6K1 kinase activity consequently ablated IGF-stimulated S6K1/ERα association, estrogen response element promoter binding and ERα target gene transcription. Moreover, site-specific ERα(S167) mutation reduced ERα target gene transcription and blocked IGF-induced colony formation. These findings support a novel link between the IGF pathway and ERα, in which the translation factor S6K1 affects transcription of ERα-regulated genes.
authors.affiliation: Department of Pharmacology, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Becker
authors.forename: Yasir H
authors.initials: YH
authors.lastname: Ibrahim
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Cui
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
authors.forename: Douglas
authors.initials: D
authors.lastname: Yee
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D007334:Insulin-Like Growth Factor I; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1