Tang Yu, Liu Rui, Zhu Jing, He Qian, Pan Chenglong, Zhou Zhongmei, Sun Jian, Li Fubing, Zhang Longlong, Shi Yujie, Yao Jing, Jiang Dewei, Chen Ceshi
Yunnan Key Laboratory of Breast Cancer Precision Medicine, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, 650118, China.
Yunnan Key Laboratory of Breast Cancer Precision Medicine, Institute of Biomedical Engineering, Kunming Medical University, Kunming, 650000, China.
Adv Sci (Weinh). 2025 Apr;12(16):e2412096. doi: 10.1002/advs.202412096. Epub 2025 Jan 30.
Basal-like breast cancer (BLBC), overlapping with the subgroup of estrogen receptor (ER), progesterone receptor (PR), and HER2 triple-negative breast cancer, has the worst prognosis and limited therapeutics. The XPO1 gene encodes nuclear export protein 1, a promising anticancer target which mediates nucleus-cytoplasm transport of nuclear export signal containing proteins such as tumor suppressor RB1 and some RNAs. Despite drugs targeting XPO1 are used in clinical, the regulation of XPO1 expression and functional mechanism is poorly understood, especially in BLBC. This study finds that KLF5 is a transcription factor of XPO1, which increases RB1 nuclear export and cell proliferation in BLBC cells. Furthermore, XPO1 interacts with the RNA-binding protein PTBP1 to export FOXO1 mRNA to cytoplasm and thus activates the FOXO1-KLF5 axis as a feedback. This work demonstrates that XPO1 inhibitor KPT-330 in combination with CDK4/6 inhibitor additively suppressed BLBC tumor growth in vivo. These results reveal a novel positive feedback regulation loop between KLF5 and XPO1 and provide a novel treatment strategy for BLBC.
基底样乳腺癌（BLBC）与雌激素受体（ER）、孕激素受体（PR）及HER2三阴性乳腺癌亚组重叠，预后最差且治疗手段有限。XPO1基因编码核输出蛋白1，这是一个很有前景的抗癌靶点，它介导含核输出信号的蛋白质（如肿瘤抑制因子RB1）及一些RNA的核质转运。尽管靶向XPO1的药物已应用于临床，但对XPO1表达的调控及其功能机制了解甚少，尤其是在BLBC中。本研究发现KLF5是XPO1的转录因子，它可增加BLBC细胞中RB1的核输出及细胞增殖。此外，XPO1与RNA结合蛋白PTBP1相互作用，将FOXO1 mRNA转运至细胞质，从而作为反馈激活FOXO1-KLF5轴。这项工作表明，XPO1抑制剂KPT-330与CDK4/6抑制剂联合使用可在体内协同抑制BLBC肿瘤生长。这些结果揭示了KLF5与XPO1之间新的正反馈调节环，并为BLBC提供了一种新的治疗策略。
