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.
Highlights
The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence after chemotherapy and radiotherapy
Recent work has indicated the plasticity of BCSCs, revealing that these cells exist in two distinct but interchangeable states: epithelial–mesenchymal transition–Cancer stem cells (CSCs), a quiescent mesenchymal type marked as EpCAM−CD49f+CD44+CD24−, and mesenchymal–epithelial transition–CSCs, an epithelial, proliferative type identified as EpCAM+CD49f+ALDH+ 2,5
Given that Tribble 3 (TRIB3) senses a variety of stress signals, and that enhanced TRIB3 expression leads to poor prognosis for breast cancer patients, we postulated that TRIB3 contributes to the pathogenesis of breast cancer via its tumor initiation capacity
Summary
The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence after chemotherapy and radiotherapy. Overexpression of FOXO1 rescued the SOX2 transcription activity in TRIB3-silenced MCF7 cells (Fig. 4c). Overexpression of FOXO1 rescued SOX2 expression in TRIB3-silenced MCF7 cells (Fig. 4f) and MDAMB-231 cells (Supplementary Fig. 4c).
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