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Oncotarget. 2017 Apr 13;8(33):54388-54401. doi: 10.18632/oncotarget.17077. eCollection 2017 Aug 15.

ZEB1 confers stem cell-like properties in breast cancer by targeting neurogenin-3.

Author information

1
Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical School of Nankai University, Tianjin 300071, China.
2
Tianjin Key Laboratory of Organ Transplantation, Tianjin First Center Hospital, Tianjin 300192, China.
3
Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
#
Contributed equally

Abstract

Cancer stem cells (CSCs) are a subpopulation of cancer cells believed to be implicated in cancer initiation, progression, and recurrence. Here, we report that ectopic expression of zinc finger E-box binding homeobox 1 protein (ZEB1) results in the acquisition of CSC properties by breast cancer cells, leading to tumor initiation and progression in vitro and in vivo. The neurogenin 3 gene (Ngn3) is a bona fide target of ZEB1, and its repression is a key factor contributing to ZEB1-induced cancer cell stemness. ZEB1 suppressed Ngn3 transcription by forming a ZEB1/DNA methyltransferase (DNMT)3B/histone deacetylase 1 (HDAC1) complex on the Ngn3 promoter, leading to promoter hypermethylation and gene silencing. The rescue of Ngn3 expression attenuated ZEB1-induced cancer stemness and symmetric CSC division. Immunohistological analysis of human breast cancer specimens revealed a strong inverse relationship between ZEB1 and NGN3 protein expression. Thus, our findings suggest ZEB1-mediated silencing of Ngn3 is required for breast tumor initiation and maintenance. Targeted therapies against the ZEB1/Ngn3 axis may be highly valuable for the prevention and treatment of breast cancer.

KEYWORDS:

ZEB1; breast cancer; neurogenin-3; stemness properties; tumor initiation

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