Downregulation of cytokeratin 18 enhances BCRP-mediated multidrug resistance through induction of epithelial-mesenchymal transition and predicts poor prognosis in breast cancer

Abstract

Multiple drug resistance (MDR) and metastasis have been identified as the two major causes of the poor prognosis of patients with breast cancer. However, the relationship between MDR and metastasis has not been characterized. Epithelial‑mesenchymal transition (EMT), a process known to promote metastasis in cancer, has been shown to be associated with the MDR phenotype of many tumor types. Reduced cytokeratin 18 (CK18) expression is thought to be one of the hallmarks of EMT, and the role of CK18 in MDR of metastatic breast cancer remains unknown. In the present study, we revealed that the expression of CK18 was significantly downregulated in breast cancer tissues and in an MDR cell line overexpressing breast cancer resistant protein (BCRP), and the presence of low levels of CK18 was associated with TNM stage, lymph node metastasis, and unfavorable survival in breast cancer patients. Further results demonstrated that CK18 stable knockdown using shRNA increased BCRP expression and induced the EMT process in human breast cancer MCF‑7 cells. Moreover, CK18 knockdown was associated with the activation of the NF‑κB/Snail signaling pathway, which has been revealed to regulate EMT and BCRP. Based on these findings, we concluded that CK18 knockdown enhanced BCRP‑mediated MDR in MCF‑7 cells through EMT induction partly via the NF‑κB/Snail pathway. These findings provide a valuable insight into the potential role of CK18 in MDR, migration and invasion of breast cancer cells. Reduced expression of CK18 may be a novel biomarker for predicting the poor prognosis of breast cancer patients.