Laboratory of Tumor Suppressor, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea. Department of Molecular Medicine, School of Medicine, Gachon University, Incheon South Korea.
Division of Convergence Technology, Center for Breast Cancer, Research Institute and Hospital, National Cancer Center 323, Ilsan-ro, Ilsandong-gu, Goyang-si Gyeonggi-do, South Korea.
Cancer Res. 2015 Apr 15;75(8):1691-702. doi: 10.1158/0008-5472.CAN-14-2041. Epub 2015 Feb 6.
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/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 T-cell factor (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 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.
乳腺癌干细胞（BCSC）对常规化疗和放疗具有抗性，这些治疗方法虽然可以破坏肿瘤团块，但不能消灭所有介导肿瘤复发的 BCSC。在本研究中，我们发现 BCSC 中的 Wnt/β-连环蛋白信号通路水平相对较高，导致其对治疗的抗性相对较高。我们设计了一种高效的小分子抑制剂 CWP232228，该抑制剂可以拮抗β-连环蛋白与核内 T 细胞因子（TCF）的结合。值得注意的是，尽管 CWP232228 通过抑制β-连环蛋白介导的转录来抑制 BCSC 和肿瘤细胞的生长，但 BCSC 的生长抑制作用强于肿瘤细胞。我们还记录到 BCSC 中胰岛素样生长因子-I（IGF-I）的表达水平明显高于肿瘤细胞，并且 CWP232228 可减弱 IGF-I 介导的 BCSC 功能。这些结果表明，CWP232228 对 BCSC 生长的抑制作用可能是通过破坏 IGF-I 活性实现的。综上所述，我们的研究结果表明，CWP232228 为乳腺癌提供了一种候选治疗药物，可优先针对 BCSC 和肿瘤细胞。
