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

// Yun Gyoung Kim 1, 2, * , Yi Na Yoon 3, 5, * , Hyang Suk Choi 1 , Ji-Hyun Kim 1 , Hyesil Seol 6 , Jin Kyung Lee 7 , Min-Ki Seong 1 , In Chul Park 3 , Kwang Il Kim 4 , Hyun-Ah Kim 1 , Jae-Sung Kim 3, 5 and Woo Chul Noh 1 1 Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea 2 Department of Surgery, Bundang Jesaeng General Hospital, Seongnam, Korea 3 Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea 4 RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea 5 Radiological and Medico-Oncological Sciences, University of Science and Technology, Seoul, Korea 6 Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea 7 Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea * These authors contributed equally to this work Correspondence to: Jae-Sung Kim, email: jaesung@kirams.re.kr Hyun-Ah Kim, email: hyunah@kcch.re.kr Keywords: breast cancer; HER2-negativebreast cancer; breast cancer stem cells; serum HER2; radioresistanceReceived: September 08, 2017 Accepted: December 04, 2017 Published: December 20, 2017 ABSTRACT Although it has been proposed that the beneficial effect of HER2-targeted therapy in HER2-negativebreast 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 radioresistancein HER2-negativebreast cancer cells and evaluated serum HER2 as a clinical biomarker for HER2 subtype conversion. We found that the CD44 + / CD24–/low BCSCs from HER2-negativebreast cancer MCF7 cells overexpressed HER2 and EGFR and showed the radioresistantphenotype. In addition, we showed that trastuzumab treatment sensitized the radioresistantphenotype of the CD44 + / CD24–/low cells with decreased levels of HER2 and EGFR, which suggested that HER2-targeted therapy in HER2-negativebreast 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-negativebreast cancer, which indicated that serum HER2 could be a clinical biomarker for the evaluation of HER2 subtype conversion in patients with recurrent HER2-negativebreast cancer. Therefore, our data have provided in vitro and in vivo evidence for the molecular subtype conversion of HER2-negativebreast cancer.