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Int J Biol Sci 2021; 17(1):247-258. doi:10.7150/ijbs.53477 This issue Cite

Research Paper

HES1 promotes breast cancer stem cells by elevating Slug in triple-negative breast cancer

Xiaoying Li^1,2, Yang Li¹, Xianqiang Du³, Xu Wang², Shu Guan², Yu Cao², Feng Jin^2✉, Feng Li^1✉

1. Department of Cell Biology, Key Laboratory of Cell Biology, National Health Commission of the PRC, and Key Laboratory of Medical Cell Biology, Ministry of Education of the PRC, China Medical University, No. 77, Puhe Road, Shenyang North New Area, 110122 Shenyang, Liaoning, China.
2. Department of Breast Surgery, The First Affiliated Hospital of China Medical University, 155 Nanjing Road, 110001 Shenyang, China.
3. Department of Breast Surgery, Affiliated Quanzhou First Hospital of Fujian Medical University, Anji Road, Quanzhou, China.

✉ Corresponding authors: Feng Li (E-mail: lifengedu.cn); Feng Jin (E-mail: jinfengedu.cn).

Abstract

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.

Keywords: stem cells, breast cancer

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