β‑catenin blockers enhance the effect of CDK4/6 inhibitors on stemness and proliferation suppression in endocrine‑resistant breast cancer cells

Wnt/β-catenin signaling is involved in endocrine resistance and stem cell-like properties of hormone receptor-positive breast cancer cells. Palbociclib is a well-known inhibitor of cyclin-dependent kinase 4 and 6 (CDK4/6 inhibitor) that downregulates the activation of retinoblastoma protein, thereby inhibiting the cell cycle in breast cancer cells. The inhibitory effects of a combination of palbociclib and ICG-001, a β-catenin small-molecule inhibitor, were investigated in tamoxifen-resistant breast cancer cell lines. Tamoxifen-resistant MCF-7 (TamR) cells were established by continuously exposing MCF-7 cells to tamoxifen. The characteristics associated with the stem cell-like property of cancer were assessed using western blotting, cell cycle analysis, and the mammosphere assay. The effects of the combination of palbociclib and ICG-001 were evaluated in control MCF-7 and TamR cell lines. Compared with control cells, TamR cells exhibited elevated levels of Nanog, Sox2, ALDH1, and p-STAT3, indicating stem cell-like characteristics, and elevated β-catenin activity. TamR cells also showed significantly higher mammosphere-forming efficiency.