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

Marc A. Becker, Yasir H. Ibrahim, Xiaojiang Cui, Adrian Lee V, Douglas Yee

Research output: Contribution to journalArticlepeer-review

92 Scopus citations


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 ERαS167 phosphorylation and did not influence ligand-dependent ERαS118 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 ERαS167 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.

Original languageEnglish (US)
Pages (from-to)516-528
Number of pages13
JournalMolecular Endocrinology
Issue number3
StatePublished - Mar 2011


  • Ligands: 17β-estradiol | fulvestrant
  • Nursa molecule pages: Nuclear receptors: Er-α


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