Wip1 Inhibition Enhances the Therapeutic Efficacy of Palbociclib in Luminal A Breast Cancer by Modulating Cell Cycle...

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors such as palbociclib have improved the treatment of hormone receptor-positive, luminal A breast cancer; however, therapeutic resistance remains a major challenge. Wild-type p53-induced phosphatase 1 (Wip1) is a negative regulator of the p53 pathway and is often over-expressed in luminal breast cancers. This study aimed to determine whether Wip1 inhibition enhances the anti-proliferative and pro-apoptotic effects of the CDK4/6 inhibitor palbociclib in luminal A breast cancer cells and to elucidate the underlying cell cycle-related mechanisms. MCF-7 cells were treated with palbociclib and Wip1 inhibitor GSK2830371, alone or in combination. Cell viability was assessed using the WST-1 assay, cell cycle distribution was analysed by flow cytometry, and apoptosis was evaluated using Annexin V/7-aminoactinomycin D staining. Expression of cell cycle regulators (CDK2, CDK4, CDK6, cyclin D1/D3, Rb, phospho-Rb) and p53-related proteins (p53, phospho-p53 Ser15, p21, p27) was determined by Western blot analysis. The combined treatment produced a concentration-dependent reduction in cell viability and a marked increase in both early and late apoptotic populations compared with monotherapies. While palbociclib alone induced G1 arrest, co-treatment with GSK2830371 shifted cells toward G2 accumulation. This was accompanied by enhanced phosphorylation of p53, up-regulation of p21 and p27, and dephosphorylation of Rb, indicating dual checkpoint engagement. These findings demonstrate that Wip1 inhibition augments palbociclib-mediated cell cycle arrest and apoptosis through modulation of the p53-Rb axis. The dual blockade of Wip1 and CDK4/6 may represent a promising therapeutic strategy for p53-proficient luminal A breast cancer.