ZFHX3 Promotes the Proliferation and Tumor Growth of ER-Positive Breast Cancer Cells Likely by Enhancing Stem-Like Features and MYC and TBX3 Transcription

• Type of Material: Article
• Authors: Ge Dong, Nankai University; Gui Ma, Nankai University; Rui Wu, Southern University of Science & Technology; Jinming Liu, Nankai University; Mingcheng Liu, Nankai University; Ang Gao, Nankai University; Xiawei Li, Nankai University; Jun A, Nankai University; Xiaoyu Liu, Southern University of Science & Technology; Zhiqian Zhang, Southern University of Science and Technology; Baotong Zhang, Emory University; Liya Fu, Nankai University; Jin-Tang Dong, Emory University
• Language: English
• Date: 2020-11-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2020 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/cancers12113415
• Title of Journal or Parent Work: CANCERS
• Volume: 12
• Issue: 11
• Start Page: 1
• End Page: 19
• Grant/Funding Information: This work was supported by a grant from the National Natural Science Foundation of China, grant number 31871466.
• Keywords: ZFHX3; NEURONAL DIFFERENTIATION; TBX3; MYC; Oncology; DELETION; Life Sciences & Biomedicine; C-MYC; PROGESTERONE-RECEPTOR; TUMORIGENESIS; MAMMARY-GLAND; GENE-EXPRESSION; cancer cells stemness; EMBRYONIC STEM; IN-VITRO; FACTOR ATBF1; Science & Technology; breast cancer
• Research Categories: Biology, Genetics; Biology, Cell; Health Sciences, Oncology

Abstract

Breast cancer is a common malignancy, but the understanding of its cellular and molecular mechanisms is limited. ZFHX3, a transcription factor with many homeodomains and zinc fingers, suppresses prostatic carcinogenesis but promotes tumor growth of liver cancer cells. ZFHX3 regulates mammary epithelial cells’ proliferation and differentiation by interacting with estrogen and progesterone receptors, potent breast cancer regulators. However, whether ZFHX3 plays a role in breast carcinogenesis is unknown. Here, we found that ZFHX3 promoted the proliferation and tumor growth of breast cancer cells in culture and nude mice; and higher expression of ZFHX3 in human breast cancer specimens was associated with poorer prognosis. The knockdown of ZFHX3 in ZFHX3-high MCF-7 cells decreased, and ZFHX3 overexpression in ZFHX3-low T-47D cells increased the proportion of breast cancer stem cells (BCSCs) defined by mammosphere formation and the expression of CD44, CD24, and/or aldehyde dehydrogenase 1. Among several transcription factors that have been implicated in BCSCs, MYC and TBX3 were transcriptionally activated by ZFHX3 via promoter binding, as demonstrated by luciferase-reporter and ChIP assays. These findings suggest that ZFHX3 promotes breast cancer cells’ proliferation and tumor growth likely by enhancing BCSC features and upregulating MYC, TBX3, and others.