Protocatechualdehyde Induced Breast Cancer Stem Cell Death via the Akt/Sox2 Signaling Pathway

Breast cancer (BC) is most frequently recognized in women and characterized by histological and molecular heterogeneity. Among the various subtypes, triple-negative BC remains the most challenging disease owing to the lack of effective molecular targets and the high frequency of breast cancer stem cells (BCSCs), which account for both recurrence and resistance to conventional treatments. Despite the availability of hormonal therapies and targeted treatments, patients still face early and late relapses, necessitating new cytotoxic and selective treatment strategies. Our study focuses on investigating the effects of protocatechualdehyde (PCA), a potent bioactive compound derived from Artemisia princeps, on CSCs in BC cells. PCA inhibited BC growth and mammosphere formation as the concentration increased. This agent decreased the fraction of the CD44⁺/CD24⁻ population, the aldehyde dehydrogenase 1A-expressing population, and the protein level of Sox2 in breast CSCs by downregulating Akt and pAkt. Moreover, PCA treatment reduced the tumor volume and weight in 4T1-challenged BALB/c mice. Collectively, our findings support the anti-tumor effect of Akt/Sox2-targeting PCA, suggesting a novel utilization of PCA in BC therapy.