HER2-Driven Breast Cancer: Role of the Chaperonin HSP90 in Modulating Response to Trastuzumab-Based Therapeutic Combinations

  • Int J Mol Sci. 2025 Jul 9;26(14):6593. doi: 10.3390/ijms26146593.
Italia Falcone  1 ,  Elena Giontella  2 ,  Stefano Giuliani  1 ,  Giulia Borghesani  2 ,  Alessandro Valenti  3 ,  Valentina Zambonin  2 ,  Sara Monteverdi  2 ,  Luisa Carbognin  4  5 ,  Emilio Bria  4  5  6 ,  Ludovica Ciuffreda  1 ,  Fabiana Conciatori  7 ,  Chiara Bazzichetto  7 ,  Serena Pedron  8 ,  Alessia Nottegar  8 ,  Sara Zanelli  2 ,  Alice Muzzarelli  2 ,  Alessandra Fabi  9 ,  Silvia Migliaccio  10 ,  Elisabetta Ferretti  10 ,  Roberto Bei  11 ,  Elena Fiorio  2 ,  Maurizio Fanciulli  1 ,  Isabella Sperduti  12 ,  Anna Caliò  8 ,  Michele Milella  2
Affiliations
  • 1. SAFU, Department of Research, Advanced Diagnostics, and Technological Innovation, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy.
  • 2. Section of Innovation Biomedicine-Oncology Area, Department of Engineering for Innovation Medicine, University of Verona and Verona University and Hospital Trust (AOUI), 37134 Verona, Italy.
  • 3. Radiology and Diagnostic Imaging Unit, Department of Clinical and Dermatological Research, San Gallicano Dermatological Institute IRCCS, 00144 Rome, Italy.
  • 4. UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00186 Roma, Italy.
  • 5. Medical Oncology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
  • 6. Medical Oncology Unit, Ospedale Isola Tiberina-Gemelli Isola, 00186 Rome, Italy.
  • 7. Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy.
  • 8. Department of Diagnostic and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy.
  • 9. Precision Medicine in Breast Cancer Unit, Scientific Directorate, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy.
  • 10. Department of Experimental Medicine, University of Rome "Sapienza", 00161 Rome, Italy.
  • 11. Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.
  • 12. Biostatistics Unit, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy.
PMID: 40724844 DOI: 10.3390/ijms26146593
Abstract

Mechanistic relationships between heat shock protein 90 (HSP90) and human epidermal growth factor receptor 2 (HER2) are complex and clinical correlations in breast Cancer remain inconsistent. We investigated the role of HSP90 expression in the response of breast Cancer cells to HER2-targeted treatments, by measuring cell viability/proliferation and protein expression after genetic and pharmacologic HER2/HSP90 modulation. HSP90 expression was also assessed by immunohistochemistry in a series of 72 metastatic, HER2+ breast Cancer patients. In HER2+ breast Cancer models (AU565, BT474, MCF7-HER2), HER2 downregulation induced HSP90 upregulation and growth inhibitory synergism between trastuzumab and docetaxel. HSP90 downregulation blunted the response to trastuzumab and docetaxel and their synergistic interactions. The addition of pertuzumab caused little additional growth inhibition, but HSP90 silencing unmasked a synergistic growth inhibitory effect with the triple combination. Conversely, HSP90 downregulation blunted the therapeutic response to trastuzumab/pertuzumab/tamoxifen or trastuzumab-emtansine. In HER2+ breast Cancer patients, high HSP90 expression was associated with significant progression-free survival benefit with the triple combination, as compared with trastuzumab and chemotherapy, although the interaction test was not statistically significant. Overall, our results highlight a mechanistic role for HSP90 in determining the response of breast Cancer cells to HER2-targeted agents and suggest that trastuzumab/pertuzumab combinations may be particularly advantageous in HSP90-high, HER2+ breast Cancer.

Keywords
HER2; HSP90; breast cancer; combination treatments; predictive biomarker; therapeutic strategies.
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