TRIB3 supports breast cancer stemness by suppressing FOXO1 degradation and enhancing SOX2 transcription

Jin-mei Yu, Wei Sun, Zhen-he Wang, Xiao Liang, Fang Hua, Ke Li, Xiao-xi Lv, Xiao-wei Zhang, Yu-ying Liu, Jiao-jiao Yu, Shan-shan Liu, Shuang Shang, Feng Wang, Zhao-na Yang, Chen-xi Zhao, Xue-ying Hou, Ping-ping Li, Bo Huang, Bing Cui () and Zhuo-Wei Hu ()
Additional contact information
Jin-mei Yu: Chinese Academy of Medical Sciences and Peking Union Medical College
Wei Sun: Chinese Academy of Medical Sciences and Peking Union Medical College
Zhen-he Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Xiao Liang: Chinese Academy of Medical Sciences and Peking Union Medical College
Fang Hua: Chinese Academy of Medical Sciences and Peking Union Medical College
Ke Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Xiao-xi Lv: Chinese Academy of Medical Sciences and Peking Union Medical College
Xiao-wei Zhang: Chinese Academy of Medical Sciences and Peking Union Medical College
Yu-ying Liu: Chinese Academy of Medical Sciences and Peking Union Medical College
Jiao-jiao Yu: Chinese Academy of Medical Sciences and Peking Union Medical College
Shan-shan Liu: Chinese Academy of Medical Sciences and Peking Union Medical College
Shuang Shang: Chinese Academy of Medical Sciences and Peking Union Medical College
Feng Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Zhao-na Yang: Chinese Academy of Medical Sciences and Peking Union Medical College
Chen-xi Zhao: Chinese Academy of Medical Sciences and Peking Union Medical College
Xue-ying Hou: Chinese Academy of Medical Sciences and Peking Union Medical College
Ping-ping Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Bo Huang: Chinese Academy of Medical Sciences and Peking Union Medical College
Bing Cui: Chinese Academy of Medical Sciences and Peking Union Medical College
Zhuo-Wei Hu: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence after chemotherapy and radiotherapy. Targeting BCSCs may ameliorate breast cancer relapse and therapy resistance. Here we report that expression of the pseudokinase Tribble 3 (TRIB3) positively associates with breast cancer stemness and progression. Elevated TRIB3 expression supports BCSCs by interacting with AKT to interfere with the FOXO1-AKT interaction and suppress FOXO1 phosphorylation, ubiquitination, and degradation by E3 ligases SKP2 and NEDD4L. The accumulated FOXO1 promotes transcriptional expression of SOX2, a transcriptional factor for cancer stemness, which in turn, activates FOXO1 transcription and forms a positive regulatory loop. Disturbing the TRIB3-AKT interaction suppresses BCSCs by accelerating FOXO1 degradation and reducing SOX2 expression in mouse models of breast cancer. Our study provides insights into breast cancer development and confers a potential therapeutic strategy against TRIB3-overexpressed breast cancer.

Date: 2019
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DOI: 10.1038/s41467-019-13700-6

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