Breast cancer stem cells in HER2-negative breast cancer cells contribute to HER2-mediated radioresistance and molecular subtype conversion: clinical implications for serum HER2 in recurrent HER2-negative breast cancer

Although it has been proposed that the beneficial effect of HER2-targeted therapy in HER2-negative breast cancer is associated with the molecular subtype conversion, the underlying mechanism and the clinical biomarkers are unclear. Our study showed that breast cancer stem cells (BCSCs) mediated HER2 subtype conversion and radioresistance in HER2-negative breast cancer cells and evaluated serum HER2 as a clinical biomarker for HER2 subtype conversion. We found that the CD44(+)/CD24(–/low) BCSCs from HER2-negative breast cancer MCF7 cells overexpressed HER2 and EGFR and showed the radioresistant phenotype. In addition, we showed that trastuzumab treatment sensitized the radioresistant phenotype of the CD44(+)/CD24(–/low) cells with decreased levels of HER2 and EGFR, which suggested that HER2-targeted therapy in HER2-negative breast cancer could be useful for targeting BCSCs that overexpress HER2/EGFR. Importantly, our clinical data showed that serial serum HER2 measurement synchronously reflected the disease relapse and the change in tumor burden in some patients who were initially diagnosed as HER2-negative breast cancer, which indicated that serum HER2 could be a clinical biomarker for the evaluation of HER2 subtype conversion in patients with recurrent HER2-negative breast cancer. Therefore, our data have provided in vitro and in vivo evidence for the molecular subtype conversion of HER2-negative breast cancer.