Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. TNBC is enriched with breast cancer stem cells (BCSCs), which are responsible for cancer initiation, cancer progression and worse prognosis. Our previous study found that HES1 was overexpressed and promoted invasion in TNBC. However, the role of HES1 in modulating BCSC stemness of TNBC remains unclear. Here, we found that HES1 upregulates Slug both in transcriptional level and in protein level. HES1 also has a positive correlation with Slug expression in 150 TNBC patient samples. TNBC patients with high HES1 and Slug levels show worse prognosis in both progression-free survival and overall survival analyses. Survival analyses indicate that the effects of HES1 on survival prognosis may depend on Slug. Furthermore, we reveal that HES1 is a novel transcriptional activator for Slug through acting directly on its promoter. Meanwhile, HES1 knockdown reduces BCSC self-renewal, BCSC population, and cancer cell proliferation in TNBC, whereas overexpression of Slug restores the oncogenic function of HES1, both in vitro and in vivo, suggesting that HES1 performs its oncogenic role through upregulating Slug. Taken together, HES1 promotes BCSC stemness properties via targeting Slug, highlighting that HES1 might be a novel candidate for BCSC stemness regulation in TNBC and providing new clues for identifying promising prognostic biomarkers and therapeutic targets of TNBC.

中文翻译：

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HES1 通过升高三阴性乳腺癌中的 Slug 来促进乳腺癌干细胞


三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的亚型。 TNBC 富含乳腺癌干细胞 (BCSC)，它们导致癌症发生、癌症进展和较差的预后。我们前期的研究发现HES1在TNBC中过度表达并促进侵袭。然而，HES1 在调节 TNBC BCSC 干性中的作用仍不清楚。在这里，我们发现 HES1 在转录水平和蛋白质水平上上调 Slug。 HES1 还与 150 个 TNBC 患者样本中的 Slug 表达呈正相关。 HES1 和 Slug 水平高的 TNBC 患者在无进展生存期和总生存期分析中均显示出较差的预后。生存分析表明 HES1 对生存预后的影响可能取决于 Slug。此外，我们发现 HES1 通过直接作用于 Slug 的启动子而成为 Slug 的新型转录激活剂。同时，HES1敲除减少了BCSC的自我更新、BCSC数量和TNBC中的癌细胞增殖，而Slug的过表达在体外和体内恢复了HES1的致癌功能，表明HES1通过上调Slug发挥其致癌作用。总而言之，HES1 通过靶向 Slug 来促进 BCSC 干性特性，强调 HES1 可能是 TNBC 中 BCSC 干性调节的新候选者，并为识别 TNBC 有前景的预后生物标志物和治疗靶点提供新线索。