Wnt/β-Catenin Small-Molecule Inhibitor CWP232228 Preferentially Inhibits the Growth of Breast Cancer Stem-like Cells

Abstract

Breast cancer stem cells (BCSC) are resistant to conventional chemotherapy and radiotherapy, which may destroy tumor masses but not all BCSC that can mediate relapses. In the present study, we showed that the level of Wnt/b-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 b-catenin to T-cell factor (TCF) in the nucleus. Notably, although CWP232228 inhibited the growth of both BCSC and bulk tumor cells by inhibiting b-catenin-mediated transcription, BCSC exhibited greater growth inhibition than bulk tumor cells. We also documented evidence of greater insulinlike 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 be 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.

Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer

“…Increased expression of hypoxia-inducible factors 1 and 2α was also shown to be associated with ALDH1 activity and believed to raise the metastatic propensity of ALDH1 high cells (6,47,48). Furthermore, increased expression of homeobox A1 and mucin 4 were associated with high ALDH1 activity, also contributing to tumor relapse and metastasis.…”

“…With the increasing evidence for such ability, researchers have attempted to demonstrate which altered genes or dysregulated gene signaling pathways potentially contribute for the tumorigenic potential of BCSCs. In fact, NOTCH, WNT/β-catenin, or Hedgehog signaling pathways were shown to be deregulated in subpopulations of these cells (5,6). With evidence forthcoming regarding the effects of the stroma and the microenvironment in breast tumor progression, several genes have also been reported to be associated with BCSCs (7).…”

A Small-Molecule Antagonist of the β-Catenin/TCF4 Interaction Blocks the Self-Renewal of Cancer Stem Cells and Suppresses Tumorigenesis

“…21) 24,25) or disrupt the transcription complex (b-catenin/CBP interaction inhibitor ICG-001, b-catenin/TCF interaction inhibitors iCRT3 and CWP232228, and b-catenin/BCL9 interaction inhibitor carnosic acid; refs. [26][27][28][29]. These studies allowed the further development of small-molecule Wnt inhibitors that entered early clinical trials, including PRI-724, CWP232291, and LGK974 (30).…”

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

“…This small molecule showed satisfactory results through preferential inhibition of growth of BCSCs and other breast tumor cells (83).…”