CSCs in Breast Cancer—One Size Does Not Fit All: Therapeutic Advances in Targeting Heterogeneous Epithelial and Mesenchymal CSCs

Unlike other breast cancer subtypes, triple-negative breast cancer (TNBC) has no specific targets and is characterized as one of the most aggressive subtypes of breast cancer that disproportionately accounts for the majority of breast cancer-related deaths. Current conventional chemotherapeutics target the bulk tumor population, but not the cancer stem cells (CSCs) that are capable of initiating new tumors to cause disease relapse. Recent studies have identified distinct epithelial-like (E) ALDH(+) CSCs, mesenchymal-like (M) CD44(+)/CD24(-) CSCs, and hybrid E/M ALDH(+)/CD44(+)/CD24(-) CSCs. These subtypes of CSCs exhibit differential signal pathway regulations, possess plasticity, and respond differently to treatment. As such, co-inhibition of different subtypes of CSCs is key to viable therapy. This review serves to highlight different pathway regulations in E and M CSCs in TNBC, and to further describe their role in disease progression. Potential inhibitors targeting E and/or M CSCs based on clinical trials are summarized for further investigation. Since future research needs to adopt suitable tumor models and take into account the divergence of E and M CSCs for the development of effective treatments, TNBC models for clinically translatable studies are further discussed.