Cancer Stem Cell-Targeted Therapeutic Approaches for Overcoming Trastuzumab Resistance in HER2-Positive Breast Cancer.

Application of the anti-HER2 drug trastuzumab has significantly improved the prognosis of patients with the HER2-positive subtype of breast cancer. However, 50% of patients with HER2 amplification relapse due to trastuzumab resistance. Accumulating evidence indicates that breast cancer is driven by a small subset of cancer-initiating cells or breast cancer stem cells (BCSCs), which have the capacity to self-renew and differentiate to regenerate the tumor cell hierarchy. Increasing data suggest that BCSCs are resistant to conventional therapy, including chemotherapy, radiotherapy, and endocrine therapy, which drives distant metastasis and breast cancer relapse. In recent years, the trastuzumab resistance of breast cancer has been closely related to the prevalence of BCSCs. Here, our primary focus is to discuss the role of epithelial-mesenchymal transition (EMT) of BCSCs in the setting of trastuzumab resistance and approaches of reducing or eradicating BCSCs in HER2-positive breast cancer. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: In HER2-positive breast tumors, trastuzumab target therapy has shown efficacy in removing non-BCSCs while failed to eradicate partial BCSCs. Targeting BCSCs might be a promising approach to prevent distant metastasis and local recurrence of HER2-positive breast cancer. Herein, we aim to discuss the mechanism of trastuzumab resistance in BCSCs of HER2-positive cancer cells and the approaches of reducing or eradicating BCSCs, especially after anti-HER2 therapy.