Abstract Background/Aim: The association between the expression of protein kinase C zeta (PKCζ) and chemotherapeutic responses among different subtypes of breast cancer has yet to be fully elucidated. The present study aimed to investigate the association between PKCζ expression and disease-specific survival (DSS) rates, with a particular focus on the influence of chemotherapy and cancer stem cell (CSC)-associated ALDH1A3 expression. Materials and Methods: Clinical and gene expression data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset (n=2,509) were analyzed using Kaplan-Meier and Cox proportional hazards models. The findings were validated using The Cancer Genome Atlas (TCGA) Pan-Cancer Atlas dataset (n=1,084). Results: In the METABRIC dataset, high PKCζ expression (PKCζhigh) was associated with poor DSS rates in patients with the normal-like, claudin-low and basal-like subtypes treated with chemotherapy. Consistent results were obtained in TCGA dataset, where PKCζhigh expression in basal-like breast cancer predicted poor prognosis, especially among patients treated with cyclophosphamide, an alkylating agent. Combined analysis further revealed that patients with high expression of both PKCζ and ALDH1A3 (PKCζhigh/ALDH1A3high) basal-like tumors treated with cyclophosphamide, doxorubicin, or fluorouracil had the worst DSS rates compared with other groups. In addition, PKCζhigh/ALDH1A3high basal-like tumors treated with anthracycline- or taxane-based regimens also exhibited poorer prognoses compared with other groups. Conclusion: PKCζ contributes to chemotherapeutic resistance, especially in patients with ALDH1A3-positive basal-like breast cancer, possibly through the regulation of CSC survival and proliferation. Moreover, PKCζ, either alone or in combination with ALDH1A3 expression, may serve as a prognostic biomarker for predicting the therapeutic efficacy of chemotherapy in basal-like breast cancer.
Nagashima et al. (2026) studied this question.