Characterization and targeting of chemoresistant triple-negative breast cancer subtypes using amino-pyridine compounds

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with limited treatment options and high relapse rates due to chemoresistance and the presence of cancer stem cells (CSCs). This study explores the molecular profile and invasive properties of two TNBC cell lines, MDA-MB-231 (Basal-Like 1; BL1 subtype) and HCC1806 (BL2 subtype), as well as their chemotherapy-resistant derivatives (doxorubicin and paclitaxel). Both cell lines exhibited CD44⁺ and CD24^-/low profiles with significant differences in epithelial-mesenchymal transition (EMT) markers. Chemoresistant variants exhibited significant changes in CSC markers, EMT genes, and ALDH activity, particularly the upregulation of CD133, suggesting its role in chemoresistance. Analysis of embryonic pathways revealed a prominent role of Sonic Hedgehog signaling, particularly in the BL2 subtype. Resistant models also exhibited increased Notch receptor expression. This study also examined novel polyamine compounds with an amino-pyridine structure. These compounds showed significant cytotoxicity against both sensitive and resistant TNBC cells, enhancing the efficacy of standard chemotherapeutics (paclitaxel and doxorubicin). Additionally, they reduced stem-like properties and self-renewal capacity of CSCs. This comprehensive characterization of TNBC cell lines and their chemoresistant variants underscores the molecular heterogeneity of TNBC and highlights potential therapeutic targets and strategies to enhance treatment efficacy and overcome resistance.