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Updated: Sep 13, 2025

Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay
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HER2-Driven Breast Cancer: Role of the Chaperonin HSP90 in Modulating Response to Trastuzumab-Based Therapeutic

Italia Falcone1, Elena Giontella2, Stefano Giuliani1

  • 1SAFU, Department of Research, Advanced Diagnostics, and Technological Innovation, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy.

International Journal of Molecular Sciences
|July 29, 2025
PubMed

Insights

Heat shock protein 90 (HSP90) influences response to human epidermal growth factor receptor 2 (HER2)-targeted therapies in breast cancer. High HSP90 expression may predict benefit from combination treatments in HER2-positive patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The interplay between heat shock protein 90 (HSP90) and human epidermal growth factor receptor 2 (HER2) in breast cancer is complex.
  • Clinical data on HSP90's role in HER2-positive breast cancer treatment response are inconsistent.

Purpose of the Study:

  • To investigate the mechanistic role of HSP90 expression in breast cancer cell response to HER2-targeted therapies.
  • To evaluate the clinical correlation between HSP90 expression and treatment outcomes in metastatic HER2-positive breast cancer patients.

Main Methods:

  • Assessed cell viability and protein expression following genetic and pharmacologic modulation of HER2 and HSP90 in HER2-positive breast cancer models.
  • Utilized immunohistochemistry to quantify HSP90 expression in 72 metastatic HER2-positive breast cancer patients.
  • Correlated HSP90 expression with treatment response to various HER2-targeted agents and chemotherapy.

Main Results:

  • HER2 downregulation led to HSP90 upregulation and synergistic growth inhibition with trastuzumab and docetaxel.
  • HSP90 downregulation diminished responses to trastuzumab, docetaxel, and their combinations.
  • HSP90 silencing revealed synergistic effects with trastuzumab, pertuzumab, and docetaxel.
  • High HSP90 expression in patients correlated with improved progression-free survival with trastuzumab/pertuzumab/chemotherapy.

Conclusions:

  • HSP90 plays a mechanistic role in breast cancer cell sensitivity to HER2-targeted therapies.
  • Trastuzumab and pertuzumab combinations may offer particular benefits in HER2-positive breast cancers with high HSP90 expression.
Keywords:
HER2HSP90breast cancercombination treatmentspredictive biomarkertherapeutic strategies

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