Sun Zicheng, Xu Huazhen, Lu Guanming, Yang Ciqiu, Gao Xinya, Zhang Jing, Liu Xin, Chen Yongcheng, Wang Kun, Guo Jianping, Li Jie
Department of Breast and Thyroid Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 510000, China.
Department of Breast and Thyroid Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities and Key Laboratory of Molecular Pathology in Tumors of Guangxi, Guangxi, 533000, China.
Adv Sci (Weinh). 2025 May;12(17):e2408106. doi: 10.1002/advs.202408106. Epub 2025 Feb 20.
Cuproptosis, a recently defined copper-dependent cell death pathway, remains largely unexplored in tumor therapies, particularly in breast cancer. This study demonstrates that triple-negative breast cancer (TNBC) bears a relatively elevated copper levels and exhibits resistance to cuproptosis. Mechanistically, copper activates the AKT signaling pathway, which inhibits ferredoxin-1 (FDX1), a key regulator of cuproptosis. AKT1-mediated FDX1 phosphorylation not only abrogates FDX1-induced cuproptosis and aerobic respiration but also promotes glycolysis. Consequently, the combination of AKT1 inhibitors and the copper ionophores synergistically alleviate TNBC tumorigenesis both in vitro and in vivo. In summary, the findings reveal a crucial mechanism underlying TNBC resistance to cuproptosis and suggest a potential therapeutic approach for TNBC.
铜死亡是一种最近定义的铜依赖性细胞死亡途径，在肿瘤治疗中，尤其是在乳腺癌治疗中，在很大程度上仍未被探索。这项研究表明，三阴性乳腺癌（TNBC）的铜水平相对升高，并且对铜死亡具有抗性。从机制上讲，铜激活AKT信号通路，该通路抑制铜死亡的关键调节因子铁氧化还原蛋白-1（FDX1）。AKT1介导的FDX1磷酸化不仅消除了FDX1诱导的铜死亡和有氧呼吸，还促进了糖酵解。因此，AKT1抑制剂和铜离子载体的组合在体外和体内均能协同减轻TNBC的肿瘤发生。总之，这些发现揭示了TNBC对铜死亡抗性的关键机制，并为TNBC提出了一种潜在的治疗方法。
