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Updated: Jun 9, 2026

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
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Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down

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TEMPORARY REMOVAL: PDZK1 disassembles HER2-HSP90 complexes to promote ubiquitin-mediated HER2 degradation and

Xuedi Cao1, Chen Qin2, Yu Guo3

  • 1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China.

Journal of Advanced Research
|June 7, 2026
PubMed

Insights

PDZK1 protein loss in HER2-positive breast cancer drives tumor progression and resistance. Restoring PDZK1 levels may improve treatment efficacy and overcome resistance in breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • HER2-positive breast cancer presents challenges with limited therapeutic response and recurrence.
  • Sustained HER2 stabilization and oncogenic signaling via HSP90 contribute to disease progression.
  • Targeting HER2 protein stability is a promising strategy to enhance treatment and suppress tumor growth.

Purpose of the Study:

  • Investigate PDZK1's role in regulating HER2 stability.
  • Evaluate the clinical and therapeutic relevance of PDZK1 in HER2-positive breast cancer.

Main Methods:

  • Integrated transcriptomic analyses and functional studies in cell and mouse models.
  • Biochemical assays (co-immunoprecipitation, ubiquitination) to define PDZK1/HER2/HSP90 interactions.
  • Analysis of PDZK1's role in tamoxifen resistance and response to fenofibrate.

Main Results:

  • Reduced PDZK1 expression correlates with poor prognosis and chemotherapy response in HER2-positive breast cancer.
  • PDZK1 disrupts the HER2/HSP90 complex, promoting HER2 degradation via ubiquitination.
  • PDZK1 loss contributes to tamoxifen resistance; fenofibrate-induced PDZK1 enhances combination therapy efficacy.

Conclusions:

  • PDZK1 regulates HER2 stability and serves as a potential biomarker for chemotherapy response and endocrine resistance.
  • Pharmacological upregulation of PDZK1 is a potential therapeutic strategy against breast cancer resistance.

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