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

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.
Mesh Terms:
Animals, Breast, Breast Neoplasms, Cell Cycle Proteins, Cell Line, Tumor, Disease Progression, Female, Forkhead Box Protein O1, Gene Expression Regulation, Neoplastic, Humans, Mice, Middle Aged, Neoplastic Stem Cells, Protein Binding, Protein-Serine-Threonine Kinases, Proteolysis, Proto-Oncogene Proteins c-akt, Repressor Proteins, SOXB1 Transcription Factors, Tissue Array Analysis, Transcription, Genetic, Xenograft Model Antitumor Assays
Nat Commun
Date: Dec. 16, 2018
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