KPNA2 silencing sensitizes triple-negative breast cancer to chemotherapy by promoting multipolar division and suppressing DNA damage repair.

Abstract

Breast cancer is one of the most common malignancies among women. Triple-negative breast cancer (TNBC) is a distinct subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Consequently, patients with TNBC do not benefit from endocrine therapy or HER2-targeted therapy, leaving conventional chemotherapy as the primary treatment option. Unfortunately, less than 30% of patients with TNBC achieve a complete response to chemotherapy, and many develop resistance, highlighting the urgent need to identify novel therapeutic targets to overcome chemoresistance. In this study, we analyzed breast cancer data from The Cancer Genome Atlas (TCGA) and discovered that KPNA2 was significantly overexpressed in the basal subtype of the PAM50 classification. Furthermore, KPNA2 expression is strongly associated with the prognosis of TNBC patients undergoing chemotherapy. Through in vitro and in vivo experiments, we demonstrated that silencing of KPNA2 enhances TNBC sensitivity to chemotherapy by promoting multipolar division and suppressing homologous recombination repair (HR), a critical DNA damage repair mechanism. Mechanistically, immunoprecipitation mass spectrometry (IP-MS) identified KIFC1 as a downstream effector of KPNA2. KPNA2 not only binds to the nuclear localization signal (NLS) of KIFC1 to regulate its nuclear translocation but also influences the ubiquitination levels of the KIFC1 protein. Additionally, RNA-seq analysis revealed that KPNA2 and KIFC1 are involved in the NF-κB signaling pathway. The KPNA2/KIFC1/NF-κB pathway/HR-related genes axis provides a comprehensive explanation of how KPNA2 influences DNA damage repair. Overall, our findings shed light on the molecular mechanisms underlying chemoresistance in TNBC. This study provides compelling evidence supporting KPNA2 as a promising therapeutic target for overcoming chemoresistance in TNBC.