Wnt/β-Catenin Small-Molecule Inhibitor CWP232228 Preferentially Inhibits the Growth of Breast Cancer Stem-like Cells
Open Access
- 14 April 2015
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 75 (8), 1691-1702
- https://doi.org/10.1158/0008-5472.can-14-2041
Abstract
Breast cancer stem cells (BCSC) are resistant to conventional chemotherapy and radiation, which may destroy tumor masses but not all BCSC that can mediate relapses. In the present study, we showed that the level of Wnt/β-catenin signaling in BCSC is relatively higher than in bulk tumor cells, contributing to a relatively higher level of therapeutic resistance. We designed a highly potent small molecule inhibitor, CWP232228, which antagonizes binding of β-catenin to TCF in the nucleus. Notably, although CWP232228 inhibited the growth of both BCSC and bulk tumor cells by inhibiting β-catenin-mediated transcription, BCSC exhibited greater growth inhibition than bulk tumor cells. We also documented evidence of greater insulin-like growth factor-I (IGF-I) expression by BCSC than by bulk tumor cells, and that CWP232228 attenuated IGF-I mediated BCSC functions. These results suggested that the inhibitory effect of CWP232228 on BCSC growth might achieved through the disruption of IGF-I activity. Taken together, our findings indicate that CWP232228 offers a candidate therapeutic agent for breast cancer that preferentially targets BCSC as well as bulk tumor cells.Keywords
Other Versions
This publication has 48 references indexed in Scilit:
- Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cellsCellular Signalling, 2013
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Thyroid hormone-mediated growth and differentiation of growth plate chondrocytes involves IGF-1 modulation of β-catenin signalingJournal of Bone and Mineral Research, 2010
- β-catenin mediates insulin-like growth factor-I actions to promote cyclin D1 mRNA expression, cell proliferation and survival in oligodendroglial culturesGlia, 2010
- The NF-κB/AKT-dependent Induction of Wnt Signaling in Colon Cancer Cells by Macrophages and IL-1βCancer Microenvironment, 2009
- Tankyrase inhibition stabilizes axin and antagonizes Wnt signallingNature, 2009
- Small molecule–mediated disruption of Wnt-dependent signaling in tissue regeneration and cancerNature Chemical Biology, 2009
- ALDH1 Is a Marker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical OutcomeCell Stem Cell, 2007
- Glioma stem cells promote radioresistance by preferential activation of the DNA damage responseNature, 2006
- Insulin-like growth factors and neoplasiaNature Reviews Cancer, 2004