NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Cancer Pub Date : 2024-09-06 DOI:10.1186/s12943-024-02102-y

Chrispus Ngule, Ruyi Shi, Xingcong Ren, Hongyan Jia, Felix Oyelami, Dong Li, Younhee Park, Jinhwan Kim, Hami Hemati, Yi Zhang, Xiaofang Xiong, Andrew Shinkle, Nathan L. Vanderford, Sara Bachert, Binhua P. Zhou, Jianlong Wang, Jianxun Song, Xia Liu, Jin-Ming Yang

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Abstract

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.

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NAC1 在三阴性乳腺癌中促进干性并调节髓源性细胞状态

三阴性乳腺癌（TNBC）是一种特别致命的乳腺癌（BC）亚型，由癌症干细胞（CSC）和免疫抑制微环境驱动。我们的研究发现，BTB/POZ基因家族成员之一的核团相关蛋白1（NAC1）通过维持肿瘤干性和影响髓源性抑制细胞（MDSCs），在TNBC中发挥着至关重要的作用。NAC1的高表达与TNBC的不良预后相关。敲除 NAC1 可减少 CSC 标记和肿瘤细胞的增殖、迁移和侵袭。此外，NAC1 还影响致癌通路，如 CD44-JAK1-STAT3 轴和免疫抑制信号（TGFβ、IL-6）。耐人寻味的是，NAC1 对肿瘤生长的影响随宿主免疫状态的不同而变化，在自然杀伤（NK）细胞功能健全的小鼠中，其致瘤性减弱，而在 NK 细胞功能缺陷的小鼠中，其致瘤性增强。这凸显了宿主免疫系统在 TNBC 进展中的重要作用。此外，MDSCs中的高NAC1水平也支持TNBC的干性。总之，这项研究表明，NAC1是一个很有前景的治疗靶点，能够同时消灭癌细胞干细胞和减轻免疫逃避。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

期刊介绍： Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.