Co-expression of PKCζ and ALDH1A3 Is Associated With Poor Chemotherapeutic Responses in Basal-like Breast Cancer.

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 (PKCζ high) 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 PKCζ high 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 (PKCζ high/ALDH1A3 high) basal-like tumors treated with cyclophosphamide, doxorubicin, or fluorouracil had the worst DSS rates compared with other groups. In addition, PKCζ high/ALDH1A3 high 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.