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

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.

• Authors: 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, Zhuo-Wei Hu
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 5720 (12 16 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 31844113 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• FOXO1 protein, human
• Forkhead Box Protein O1
• Repressor Proteins
• SOX2 protein, human
• SOXB1 Transcription Factors
• TRIB3 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Breast (pathology)
• Breast Neoplasms (genetics, pathology)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Disease Progression
• Female
• Forkhead Box Protein O1 (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Middle Aged
• Neoplastic Stem Cells (pathology)
• Protein Binding
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proteolysis
• Proto-Oncogene Proteins c-akt (metabolism)
• Repressor Proteins (metabolism)
• SOXB1 Transcription Factors (genetics)
• Tissue Array Analysis
• Transcription, Genetic
• Xenograft Model Antitumor Assays