Work

SB431542, a Selective Inhibitor of the TGF-β Type I Receptor, Enhances Doxorubicin Antitumor Activity via p63 Activation in Mutant p53 Breast Cancer Cells

Year: 2025

Type: article

Abstract: Background: TP53 gene mutations are common in breast cancer and are linked to chemoresistance. p63, a p53 family member, can induce apoptosis independently of p53, representing a potential therapeutic target in TP53-mutant tumors. This study evaluated the synergistic effects of SB431542, a TGF-β type I receptor inhibitor, and doxorubicin in TP53-mutant breast cancer cells. Methods: Isoform-specific RT-PCR was used to assess TAp63 and ΔNp63 expression following SB431542 treatment in T47D, MDA-MB-231, and MDA-MB-468 cells. Cell viability was assessed using the CCK8 assay. Synergistic interaction was quantified using the Coefficient of Drug Interaction (CDI). Caspase-3/7 activity assays and immunocytochemistry analyses were performed to evaluate apoptotic signaling and p63 expression. Inhibition studies using PETα, a p53-family inhibitor, and a pan-caspase inhibitor were conducted to determine the pathway dependency of the observed effects. Results: SB431542 selectively increased TAp63 but not ΔNp63 expression in all three TP53-mutant breast cancer cells. GAS6, a TAp63 target, was also upregulated by SB431542. Treatment with SB431542 and doxorubicin used in combination significantly reduced cell viability (CDI 0.54–0.63), increased caspase activity, and enhanced p63 expression. The anticancer effect was significantly reduced by co-treatment with either the p53-family inhibitor or the pan-caspase inhibitor, confirming that the cytotoxic response was mediated through TAp63 and caspase activation. Conclusions: SB431542 potentiates doxorubicin-induced apoptosis in TP53-mutant breast cancer cells by upregulating TAp63 and activating caspase-dependent pathways. These findings suggest that targeting the TGF-β/TAp63 signaling axis may offer a novel therapeutic approach to overcome chemoresistance in aggressive, TP53-mutant breast cancers.

Source: Frontiers in Bioscience-Landmark

DOI: 10.31083/fbl45389