PDZK1 disassembles HER2-HSP90 complexes to promote ubiquitin-mediated HER2 degradation and overcome therapy resistance

Introduction Limited therapeutic response and disease recurrence remain major challenges in HER2-positive breast cancer, largely driven by sustained HER2 stabilization and persistent oncogenic signaling mediated by HSP90. Therefore, targeting HER2 protein stability may represent a promising strategy to improve therapeutic responsiveness and suppress HER2-driven tumor progression. Objectives This study investigated the mechanisms by which PDZK1 regulates HER2 stability and evaluated its clinical and therapeutic relevance in HER2-positive breast cancer. Methods Integrated transcriptomic analyses identified PDZK1 as a potential tumor suppressor during HER2-positive breast cancer progression and recurrence. Functional studies using 2D/3D cell assays, xenograft and Pdzk1 -deficient mouse models, tissue microarrays, and immunohistochemistry were performed to evaluate PDZK1 function. Molecular docking, co-immunoprecipitation, GST pull-down, and ubiquitination assays were used to characterize PDZK1/HER2/HSP90 interactions. RNA-seq, PAM50 classification, tamoxifen-resistant models, and synergy analyses were additionally conducted to investigate the relationship between PDZK1 deficiency and endocrine resistance. Results PDZK1 expression was significantly reduced in HER2-positive breast cancer and was associated with poor prognosis and unfavorable chemotherapy response. Mechanistically, PDZK1 directly bound to HER2, disrupted the HER2/HSP90 complex, and recruited the HSP70/CHIP complex to promote HER2 polyubiquitination and degradation. PDZK1 loss also promoted tamoxifen resistance in ER-positive breast cancer models. Furthermore, pharmacological induction of PDZK1 by fenofibrate enhanced the efficacy of combinatorial therapeutic regimens in resistant breast cancer models. These findings suggest PDZK1 may serve as a potential biomarker associated with chemotherapy response and endocrine resistance. Conclusions PDZK1 functions as a regulator of HER2 stability and may serve as a potential biomarker and therapeutic target in HER2-positive breast cancer. Pharmacological upregulation of PDZK1 may represent a promising combinatorial therapeutic strategy for overcoming therapeutic resistance in breast cancer.