ßcatenin blockers enhance the effect of CDK4/6 inhibitors on stemness and proliferation suppression in endocrineresistant breast cancer cells.
Oncol Rep
; 48(1)2022 Jul.
Article
in En
| MEDLINE
| ID: mdl-35656884
ABSTRACT
Wnt/ßcatenin signaling is involved in endocrine resistance and stem celllike properties of hormone receptorpositive breast cancer cells. Palbociclib is a wellknown inhibitor of cyclindependent 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 ICG001, a ßcatenin smallmolecule inhibitor, were investigated in tamoxifenresistant breast cancer cell lines. Tamoxifenresistant MCF7 (TamR) cells were established by continuously exposing MCF7 cells to tamoxifen. The characteristics associated with the stem celllike property of cancer were assessed using western blotting, cell cycle analysis, and the mammosphere assay. The effects of the combination of palbociclib and ICG001 were evaluated in control MCF7 and TamR cell lines. Compared with control cells, TamR cells exhibited elevated levels of Nanog, Sox2, ALDH1, and pSTAT3, indicating stem celllike characteristics, and elevated ßcatenin activity. TamR cells also showed significantly higher mammosphereforming efficiency. Several markers of stem celllike nature of TamR cells showed reduced levels upon treatment of cells with the drug combination; there was a greater reduction in the levels of these markers when the cells were treated with the combination than in the case where cells were treated with one of the drugs individually (combination index value for 25 µM palbociclib and 50 µM ICG001 was 1.1±0.02). TamR cells treated with the palbociclib and ICG001 combination demonstrated significantly reduced cell proliferation and mammosphereforming efficiency compared with the cells treated with one of these drugs. The combination of the drugs could additively inhibit proliferation and suppress stem celllike characteristics. These results suggest that ßcatenin plays a role in endocrineresistant breast cancer; the inhibition of ßcatenin and CDK4/6 together can overcome endocrine resistance in breast cancer cells.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Breast Neoplasms
/
Drug Resistance, Neoplasm
/
Beta Catenin
Limits:
Female
/
Humans
Language:
En
Journal:
Oncol Rep
Journal subject:
NEOPLASIAS
Year:
2022
Document type:
Article