The TrkB+ cancer stem cells contribute to post-chemotherapy recurrence of triple-negative breast cancers in an orthotopic mouse model

Abstract

Cancer stem cells (CSCs) are believed to have a crucial role in triple-negative breast cancer (TNBC) recurrence. However, the exact mechanisms that are functionally critical in CSCs-mediated recurrence remain unclear. Here, we showed that CSCs derived from recurrent TNBCs are endowed with increased self-renewal capacity as compared with those from the matched primary lesions. Using patient-derived specimens, we demonstrated the existence of paracrine brain-derived neurotrophic factor (BDNF) signaling between differentiated recurrent TNBC cells and CSCs characterized by the expression of TrkB, the receptor of BDNF. We showed that paclitaxel induced BDNF expression and apoptosis simultaneously in a cell cycle-dependent manner. BDNF promotes the self-renewal potential of the TrkB+CSCs through induction of KLF4. The TrkB+CSCs represent a particular subset indispensable for TNBC relapse. In line with this, TrkB is proved to be a superior predictor for TNBC recurrence. Using a genetically engineered mouse model of TNBC, we observed that ablation of the TrkB+CSCs potentially prevents relapse of malignant tumors. Further preclinical investigation of this promising approach may lead to development of a novel therapeutic strategy to improve the devastating prognosis of TNBC patients.