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

Marc A Becker1, Yasir H Ibrahim, Xiaojiang Cui

  • 1Department of Pharmacology, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.

Molecular Endocrinology (Baltimore, Md.)
|February 5, 2011
PubMed

Insights

The mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) pathway critically links insulin-like growth factor (IGF) signaling to estrogen receptor alpha (ERα) in breast cancer, impacting cell proliferation and motility.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Endocrinology

Background:

  • The insulin-like growth factor (IGF) pathway promotes breast cancer malignancy.
  • Estrogen receptor alpha (ERα) signaling is crucial for IGF-mediated growth.
  • Mammalian target of rapamycin (mTOR) and S6 kinase 1 (S6K1) are implicated in IGF signaling.

Purpose of the Study:

  • To elucidate the role of the mTOR/S6K1 axis in IGF and ERα cross-talk.
  • To investigate the downstream effects of IGF signaling on ERα activity.
  • To identify novel therapeutic targets in ERα-positive breast cancer.

Main Methods:

  • Utilized small molecule inhibitors and targeted knockdown of S6K1.
  • Assessed ERα phosphorylation at specific sites (S167 and S118).
  • Examined S6K1/ERα association, DNA binding, and gene transcription.

Main Results:

  • mTOR/S6K1 inhibition differentially affected IGF-induced cell proliferation and motility.
  • S6K1 inhibition blocked IGF-induced ERα(S167) phosphorylation but not ERα(S118) phosphorylation.
  • Inhibition of S6K1 ablated IGF-stimulated ERα promoter binding and target gene transcription.
  • ERα(S167) mutation reduced ERα target gene transcription and blocked IGF-induced colony formation.

Conclusions:

  • The mTOR/S6K1 axis is a critical mediator of IGF and ERα cross-talk in breast cancer.
  • S6K1 directly influences ERα transcriptional activity via phosphorylation at S167.
  • This pathway represents a potential therapeutic target for ERα-positive breast cancers.

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