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.

Single-Cell Probe Force Studies to Identify Sox2 Overexpression-Promoted Cell Adhesion in MCF7 Breast Cancer Cells

“…Furthermore, Sox2 increases the expression of another transcription factor, Sox9, which is also implicated in maintenance of luminal progenitor and breast CSCs [29,32]. Other reports have correlated high levels of Sox2 expression with increased survival, self-renewal capacity, and metastatic outgrowth in other types of tumors as well [33][34][35][36]. We hypothesized that the overexpression of Sox2 leads to changes in the expression of proteins related to breast cancer cell adhesion.…”

Functional characterization of SOX2 as an anticancer target

“…In general, SOX2 positively or negatively regulates proliferative or antiproliferative signaling pathways, respectively, leading to enhanced proliferation, survival, and tumorigenesis its downstream target FoxO1, which inhibits SOX2 transcription. 48 The expression of pseudokinase Tribble 3 promotes breast cancer stemness and progression by activating the AKT1-FoxO1-SOX2 axis. 48 The cyclin-dependent kinase inhibitor p21 is capable of controlling adult neural stem cell expansion by directly binding to the SOX2 enhancer and negatively regulates SOX2 transcription.…”

“…48 The expression of pseudokinase Tribble 3 promotes breast cancer stemness and progression by activating the AKT1-FoxO1-SOX2 axis. 48 The cyclin-dependent kinase inhibitor p21 is capable of controlling adult neural stem cell expansion by directly binding to the SOX2 enhancer and negatively regulates SOX2 transcription. 49 Recently, a homeobox-containing transcription factor, muscle segment homeobox-2 (MSX2) was found to destabilize the pluripotency circuitry by acting as a transcription repressor to directly bind to the SOX2 promoter and inhibit SOX2 transcription, which is essential for mesendoderm differentiation.…”

Proteolysis targeting chimeras (PROTACs) in cancer therapy

“…TFs, as well as nuclear receptors, have been involved in the oncogenic generation of several malignancies. In fact, genomic alterations in c-MYC, FOXO1 or the androgen receptor (AR) have been described in neuroblastoma, breast or prostate cancer, respectively [ 6 , 8 ]. A therapeutic strategy that has been contemplated is the reduction of the expression of these proteins by inducing their degradation.…”