The IGF pathway regulates ERα through a S6K1-dependent mechanism in breast cancer cells

Mol Endocrinol. 2011 Mar;25(3):516-28. doi: 10.1210/me.2010-0373. Epub 2011 Feb 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Blotting, Western
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromatin Immunoprecipitation
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Humans
  • Immunoprecipitation
  • Insulin-Like Growth Factor I / pharmacology*
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism*

Substances

  • Estrogen Receptor alpha
  • estrogen receptor alpha, human
  • Insulin-Like Growth Factor I
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1