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Estrogen-induced FXR1 promotes endocrine resistance and bone metastasis in breast cancer via BCL2 and GPX4

Yinzhong Shang1,2, Tingfang Cao1, Xin Ma3

  • 1Department of Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, National Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, Hefei, China.

Frontiers in Cell and Developmental Biology
|April 8, 2025
PubMed

Insights

Estrogen signaling dysregulation drives anti-estrogen resistance in ER+ breast cancer. FXR1 protein was identified as a key driver, and targeting it may overcome resistance and treat bone metastasis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Estrogen signaling pathway is crucial in ER+ mammary carcinoma.
  • Dysregulation of this pathway leads to anti-estrogen resistance and bone metastasis.
  • Identifying novel therapeutic targets is essential for improving treatment outcomes.

Purpose of the Study:

  • To identify novel molecular targets involved in anti-estrogen resistance in ER+ breast cancer.
  • To elucidate the mechanism by which FXR1 contributes to therapeutic resistance.
  • To evaluate FXR1 antagonism as a potential therapeutic strategy for bone metastases.

Main Methods:

  • Quantitative proteomic screening to identify differentially expressed proteins.
  • Investigated the role of FXR1 in regulating apoptosis and ferroptosis.
  • Utilized cell culture models of anti-estrogen resistant breast cancer.
  • Assessed the efficacy of FXR1 depletion and combination therapies in vitro.

Main Results:

  • FXR1 was identified as an estrogen-regulated RNA-binding protein promoting anti-estrogen resistance.
  • Estrogen and IGF1 enhance FXR1 translation via the PI3K/AKT/mTOR/EIF4E pathway.
  • FXR1 promotes resistance to apoptosis and ferroptosis by regulating BCL2 and GPX4 mRNA.
  • FXR1 depletion resensitizes resistant cells to tamoxifen and synergizes with ferroptosis inducers.

Conclusions:

  • FXR1 is a critical mediator of anti-estrogen resistance and ferroptosis resistance in ER+ breast cancer.
  • Targeting FXR1 presents a promising therapeutic strategy to overcome tamoxifen resistance.
  • FXR1 antagonism offers a potential approach to treat bone metastases in ER+ breast cancer.
Keywords:
FXR1anti-estrogen resistanceapoptosisestrogenferroptosis

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