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Updated: Jul 9, 2025

Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
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Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells

Published on: February 21, 2014

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PSMD14 stabilizes estrogen signaling and facilitates breast cancer progression via deubiquitinating ERα

Penghe Yang1,2, Xiao Yang3,4, Dehai Wang5

  • 1Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, 453003, Henan Province, PR China.

Oncogene
|November 28, 2023
PubMed

Insights

Researchers identified PSMD14 as a key deubiquitinase driving breast cancer progression by stabilizing estrogen receptor alpha (ERα). Inhibiting PSMD14 restores tamoxifen sensitivity in resistant cancers, offering a new therapeutic strategy.

Area of Science:

  • Molecular Oncology
  • Endocrinology
  • Cancer Therapeutics

Background:

  • Estrogen receptor alpha (ERα) over-activation drives luminal breast cancers, treatable with selective estrogen receptor modulators (SERMs) like tamoxifen.
  • Endocrine resistance remains a significant challenge in breast cancer treatment.
  • Post-translational modifications of ERα, particularly ubiquitination, are increasingly implicated in endocrine resistance.

Purpose of the Study:

  • To identify key deubiquitinases regulating ERα stability and signaling in breast cancer.
  • To investigate the role of PSMD14 in breast cancer progression and endocrine resistance.
  • To evaluate PSMD14 inhibition as a potential therapeutic strategy for luminal breast cancer.

Main Methods:

  • Conducted a deubiquitinase siRNA library screen to identify regulators of ERα.
  • Utilized in vitro and in vivo models of breast cancer, including endocrine-resistant models.
  • Employed molecular techniques such as Western blotting, ChIP assays, and gene expression analysis.
  • Investigated the effect of PSMD14 inhibition using the pharmaceutical agent Thiolutin.

Main Results:

  • PSMD14 was identified as a critical deubiquitinase stabilizing ERα and promoting breast cancer progression.
  • Inhibition of PSMD14 with Thiolutin blocked tumorigenesis and sensitized resistant breast cancer models to tamoxifen.
  • PSMD14 de-stabilized the resistant ERα (Y537S) mutant and restored tamoxifen sensitivity.
  • PSMD14 reduces K48-linked poly-ubiquitination of ERα, enhancing its transcriptome.
  • A positive feedback loop exists where ERα promotes PSMD14 transcription, and PSMD14 stabilizes ERα.

Conclusions:

  • PSMD14 plays a crucial role in ERα signaling and breast cancer progression.
  • Targeting PSMD14 represents a promising therapeutic strategy to overcome endocrine resistance in luminal breast cancer.
  • The identified PSMD14-ERα feedback loop offers a novel target for combination therapies.

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