Cai Yufan, Du Junxian, Wang Haiyu, Shen Lei, Xu Zujing, Zhaoxiong Yizhou, Gong Zheng, Zhu You, Wu Chuxun, Cai Jialiang, Zhang Peiling, Chen Shiping, Dai Zhi, Huang Run, Zhu Wei
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
The International Peace Maternity & Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Oncogene. 2025 Sep 18. doi: 10.1038/s41388-025-03503-z.
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.
乳腺癌是女性中最常见的恶性肿瘤之一。三阴性乳腺癌（TNBC）是乳腺癌的一种独特亚型，其特征是缺乏雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子受体2（HER2）。因此，TNBC患者无法从内分泌治疗或HER2靶向治疗中获益，传统化疗成为主要的治疗选择。不幸的是，不到30%的TNBC患者对化疗有完全反应，许多患者会产生耐药性，这凸显了识别新的治疗靶点以克服化疗耐药性的迫切需求。在本研究中，我们分析了来自癌症基因组图谱（TCGA）的乳腺癌数据，发现KPNA2在PAM50分类的基底亚型中显著过表达。此外，KPNA2表达与接受化疗的TNBC患者的预后密切相关。通过体外和体内实验，我们证明沉默KPNA2可通过促进多极分裂和抑制同源重组修复（HR，一种关键的DNA损伤修复机制）来增强TNBC对化疗的敏感性。从机制上讲，免疫沉淀质谱（IP-MS）鉴定出KIFC1是KPNA2的下游效应分子。KPNA2不仅与KIFC1的核定位信号（NLS）结合以调节其核转位，还影响KIFC1蛋白的泛素化水平。此外，RNA测序分析表明KPNA2和KIFC1参与NF-κB信号通路。KPNA2/KIFC1/NF-κB通路/HR相关基因轴全面解释了KPNA2如何影响DNA损伤修复。总体而言，我们的研究结果揭示了TNBC化疗耐药性的分子机制。本研究提供了有力证据，支持将KPNA2作为克服TNBC化疗耐药性的有前景的治疗靶点。
