ERCC6L facilitates the onset of mammary neoplasia and promotes the high malignance of breast cancer by accelerating cell cycle

Abstract

Abstract Breast cancer (BRCA) is the first cause of morbidity and the second cause of death in female malignant tumors. Although available drugs have been approved for the corresponding breast cancer subtypes (ER Positive, HER2+) currently, there are still no effective targeted drugs and treatment strategies for metastatic breast cancer or triple-negative breast cancer that lack targets. Therefore, it’s urgent to discover new potential targets. ERCC6L is an essential protein involved in chromosome separation during cell mitosis. However, it’s not unclear the effect of ERCC6L on tumorigenesis and progression of breast cancer. Here, we found that ERCC6L was highly expressed in breast cancer, especially in TNBC, which was closely related to poor outcomes of patients. ERCC6L conditional knockout mouse model was first carried out in this study and results that ERCC6L was required for the development of mammary gland and the tumorigenesis and progression of mammary gland cancers were confirmed. In vitro cell culture, ERCC6L acted as a tumor promoter in the malignant progression of breast cancer cells. Overexpression of ERCC6L could promote cell proliferation, migration and invasion, while knockdown of ERCC6L can cause the opposite results. Mechanistically, ERCC6L accelerated the cell cycle by regulating the G2/M checkpoint signaling pathway. Additionally, we demonstrated that there is an interaction between ERCC6L and KIF4A, both of which are a pair of closely related factors in mitosis and involved in the malignant progression of breast cancer. Taken together, ERCC6L may be used as a promising target for the treatment of BRCA.