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ETHE1 Accelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2α/ATF4 Signaling

Shao-Ying Yang1,2,3, Li Liao1,2,3, Shu-Yuan Hu1

  • 1Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.

International Journal of Molecular Sciences
|October 14, 2023
PubMed

Insights

ETHE1 promotes triple-negative breast cancer (TNBC) metastasis by enhancing eIF2α phosphorylation and ATF4 expression. Targeting ETHE1 or eIF2α phosphorylation with ISRIB offers a novel therapeutic strategy for TNBC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metastasis Research

Background:

  • Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options.
  • Understanding TNBC metastasis mechanisms is crucial for developing effective therapies.
  • The role of ETHE1, linked to ethylmalonic encephalopathy, in TNBC is currently unknown.

Purpose of the Study:

  • To investigate the function and mechanism of ETHE1 in triple-negative breast cancer progression.
  • To identify potential therapeutic targets for TNBC metastasis.

Main Methods:

  • Generation of stable cell lines with ETHE1 overexpression or knockdown.
  • In vitro assays for cell migration and invasion.
  • In vivo studies of lung metastasis in mouse models.
  • Mass spectrometry for molecular mechanism analysis.
  • Western blotting and co-immunoprecipitation to study protein interactions.

Main Results:

  • ETHE1 overexpression significantly promoted TNBC cell migration, invasion, and lung metastasis in vivo, without affecting proliferation or tumor growth.
  • ETHE1's pro-metastatic effect was independent of its enzymatic activity.
  • ETHE1 enhanced eIF2α phosphorylation by promoting the eIF2α-GCN2 interaction, leading to increased ATF4 expression.
  • Inhibition of eIF2α phosphorylation or ATF4 knockdown partially reversed ETHE1's pro-metastatic effects.

Conclusions:

  • ETHE1 plays a critical role in promoting TNBC metastasis through the eIF2α/ATF4 pathway.
  • ETHE1 represents a potential therapeutic target for aggressive TNBC.
  • ISRIB, an inhibitor of eIF2α phosphorylation, shows promise for treating ETHE1-driven TNBC metastasis.
Keywords:
cancer invasion and metastasisethylmalonic encephalopathy protein 1integrated stress responsetriple-negative breast cancer

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