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RSK-Mediated Non-canonical Activation of EphA2 by Tamoxifen

Keisuke Yonehara1,2, Yue Zhou1, Jun-Ichiro Takahashi1

  • 1Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama.

Biological & Pharmaceutical Bulletin
|February 3, 2022
PubMed

Insights

Tamoxifen, a breast cancer treatment, can promote tumor cell migration via the MAPK/ERK pathway, independent of estrogen receptors. This study reveals new insights into tamoxifen

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Tamoxifen is a standard treatment for estrogen receptor α (ERα)-positive breast cancer, reducing mortality and recurrence.
  • However, tamoxifen resistance and increased endometrial cancer risk necessitate understanding its adverse effects.
  • Tamoxifen can activate mitogen-activated protein kinase (MAPK) independently of ERα.

Purpose of the Study:

  • To investigate tamoxifen's effects on MAPK-mediated, non-canonical activation of EphA2.
  • To elucidate the role of this pathway in regulating cancer cell migration.

Main Methods:

  • Utilized HeLa and ERα-negative MDA-MB-231 breast cancer cells.
  • Examined tamoxifen's impact on EphA2 phosphorylation at Ser-897 via the MEK-ERK-RSK pathway.
  • Assessed tamoxifen's effect on cell migration and EphA2 localization.

Main Results:

  • Tamoxifen induced rapid EphA2 phosphorylation at Ser-897 through the MEK-ERK-RSK pathway in HeLa cells.
  • Tamoxifen significantly enhanced MDA-MB-231 cell migration in an RSK- and EphA2-dependent manner.
  • Phosphorylated EphA2 was internalized and relocalized to the plasma membrane, including lamellipodia, dependent on RSK.

Conclusions:

  • Tamoxifen can promote tumor cell migration through non-canonical EphA2 activation via the MAPK/ERK pathway.
  • These findings offer novel insights into the potential tumor-promoting activities of tamoxifen.
  • Understanding these mechanisms is crucial for managing tamoxifen resistance and side effects.
Keywords:
EphA2estrogen receptorextracellular signal-regulated kinase (ERK)migrationribosomal S6 kinase (RSK)tamoxifen

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