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Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through

Phillip A Geter1, Amanda W Ernlund1, Sofia Bakogianni1

  • 1Department of Microbiology, Alexandria Center for Life Science, New York University School of Medicine, New York, New York 10016, USA.

Genes & Development
|December 23, 2017
PubMed

Insights

Tamoxifen resistance in estrogen receptor-positive breast cancer involves reprogramming mRNA translation, driven by increased eIF4E and Runx2. Restoring tamoxifen sensitivity requires reducing eIF4E or mTOR activity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Estrogen receptor-positive (ER+) breast cancer is common and often treated with tamoxifen.
  • Tamoxifen resistance is a major cause of mortality in breast cancer patients.
  • Understanding resistance mechanisms is crucial for improving treatment outcomes.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying tamoxifen resistance in ER+ breast cancer.
  • To identify key regulators of translational reprogramming in tamoxifen-resistant cells.
  • To explore strategies for overcoming tamoxifen resistance.

Main Methods:

  • Utilized cell lines, patient-derived xenografts, and patient tumor tissues.
  • Employed small molecule inhibitors, phospho-mimetic proteins, and genome-wide transcription/translation studies.
  • Investigated the roles of eIF4E, mTOR, MNK, and Runx2 in tamoxifen resistance.

Main Results:

  • Tamoxifen resistance is associated with selective mRNA translational reprogramming, involving Runx2 and other mRNAs.
  • Increased expression and hyperactive mTOR signaling lead to enhanced eIF4E availability and phosphorylation at Ser209 via MNK activity.
  • Silencing Runx2 or reducing eIF4E/mTOR activity/MNK phosphorylation restores tamoxifen sensitivity.
  • Tamoxifen-resistant tumors show increased MNK phosphorylation of eIF4E.

Conclusions:

  • Selective mRNA translational reprogramming, mediated by eIF4E, mTOR, and MNK pathways, is a key mechanism of tamoxifen resistance in ER+ breast cancer.
  • Runx2 plays a significant role in promoting tamoxifen resistance and metastasis.
  • Targeting eIF4E, mTOR, or MNK activity offers potential therapeutic strategies to overcome tamoxifen resistance.
Keywords:
ER+ breast cancercap-dependent translationeIF4Etamoxifentranslation initiationtranslational control

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