Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
Present Address: Department of Cell Biology and Genetics, Shanxi Medical University, Taiyuan, Shanxi, China.
Mol Cancer. 2024 Sep 6;23(1):188. doi: 10.1186/s12943-024-02102-y.
Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion. Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFβ, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression. In addition, high NAC1 level in MDSCs also supports TNBC stemness. Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.
三阴性乳腺癌（TNBC）是一种特别致命的乳腺癌亚型，由癌症干细胞（CSCs）和免疫抑制微环境驱动。我们的研究表明，BTB/POZ 基因家族的成员核仁相关蛋白 1（NAC1）通过维持肿瘤干细胞特性和影响髓源性抑制细胞（MDSCs）在 TNBC 中发挥关键作用。高 NAC1 表达与 TNBC 预后不良相关。NAC1 敲低降低了 CSC 标志物和肿瘤细胞的增殖、迁移和侵袭。此外，NAC1 还影响癌基因途径，如 CD44-JAK1-STAT3 轴和免疫抑制信号（TGFβ、IL-6）。有趣的是，NAC1 对肿瘤生长的影响因宿主免疫状态而异，在自然杀伤（NK）细胞功能正常的小鼠中肿瘤生成能力降低，但在 NK 细胞缺陷的小鼠中肿瘤生成能力增加。这突出了宿主免疫系统在 TNBC 进展中的重要作用。此外，MDSCs 中的高 NAC1 水平也支持 TNBC 干性。总之，这项研究表明 NAC1 是一个有前途的治疗靶点，能够同时根除 CSCs 并减轻免疫逃逸。
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