Blockade of Wnt/β-catenin signaling suppresses breast cancer metastasis by inhibiting CSC-like phenotype

Abstract

The identification of cancer stem cells (CSCs) represents an important milestone in the understanding of chemodrug resistance and cancer recurrence. More specifically, some studies have suggested that potential metastasis-initiating cells (MICs) might be present within small CSC populations. The targeting and eradication of these cells represents a potential strategy for significantly improving clinical outcomes. A number of studies have suggested that dysregulation of Wnt/β-catenin signaling occurs in human breast cancer. Consistent with these findings, our previous data have shown that the relative level of Wnt/β-catenin signaling activity in breast cancer stem cells (BCSCs) is significantly higher than that in bulk cancer cells. These results suggest that BCSCs could be sensitive to therapeutic approaches targeting Wnt/β-catenin signaling pathway. In this context, abnormal Wnt/β-catenin signaling activity may be an important clinical feature of breast cancer and a predictor of poor survival. We therefore hypothesized that Wnt/β-catenin signaling might regulate self-renewal and CSC migration, thereby enabling metastasis and systemic tumor dissemination in breast cancer. Here, we investigated the effects of inhibiting Wnt/β-catenin signaling on cancer cell migratory potential by examining the expression of CSC-related genes, and we examined how this pathway links metastatic potential with tumor formation in vitro and in vivo.

Colon cancers carrying BRAF V600E and β-catenin T41A activating mutations are resistant to numerous common anticancer drugs

“…By contrast, activation of the Wnt/β-catenin pathway led to increased stemness of cancer cells and drug resistance (30)(31)(32)(33). Wnt/β-catenin signaling was constitutively activated in breast cancer stem cells, and blockade of the Wnt/β-catenin pathway inhibited cancer metastasis (30). Elevated β-catenin activity promoted carboplatin resistance in the ovarian cancer A2780 cell line (31).…”

“…A large-scale phase III trial (PETACC-8 trial) demonstrated that the BRAF V600E mutation led to shorter disease-free survival and overall survival times in patients with microsatellite-stable colon cancers treated with a combination of leucovorin, fluorouracil and oxaliplatin, with or without cetuximab (29). By contrast, activation of the Wnt/β-catenin pathway led to increased stemness of cancer cells and drug resistance (30)(31)(32)(33). Wnt/β-catenin signaling was constitutively activated in breast cancer stem cells, and blockade of the Wnt/β-catenin pathway inhibited cancer metastasis (30).…”

Differential Effects of Dishevelled 2 and 3 on TCF/LEF- Mediated Transcriptional Activation in Wnt-3a-Treated Breast Cancer Cell Line MDA-MB-231

“…4,8 Inhibition of the Wnt pathway reduced stem-like cell activity in patient-derived metastatic breast cancer cells. 9 Thus, these studies provide evidence to support the potential of Wnt-targeted therapeutics for breast cancer patients. 4,9 Dishevelled (Dvl) proteins are central mediators of the Wnt signalling pathway which plays an important role in embryonic development, generation of cell polarity and cell specification.…”

Targeting Cellular Signaling Pathways in Breast Cancer Stem Cells and its Implication for Cancer Treatment

“…In colon cancer and melanoma, genetic alterations of β-catenin and adenomatous polyposis coli (APC) have been identified; however, it has not had a significant impact on breast cancer cells (13). In BCSC, the role of Wnt signaling has been associated with the maintenance of stem cell properties: inhibition of WNT1 alters the phenotype to CD44 + CD24 − ALDH1 − , reducing in vitro and in vivo tumor formation and cellular migration (14).…”