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

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

  • Front Biosci (Landmark Ed). 2025 Dec 18;30(12):45389. doi: 10.31083/FBL45389.
Yu-Ling Kou 1,  Yu-Jie Liu 1,  Tzu-Chi Hsu 1,  Kuan-Yo Wu 2,  Sih-Tong Chen 3,  Jing-Yan Chen 3,  Kuan-Yu Lin 3,  Hsiao-Hsuan Wang 3,  Yi-Ting Cheng 3,  Chia-Chi Chen 4 5 6,  Bi-He Cai 7
Affiliations

Affiliations

  • 1 Department of Medical Laboratory Science, I-Shou University, 82445 Kaohsiung, Taiwan.
  • 2 Department of Biomedical Engineering, I-Shou University, I-Shou University, 82445 Kaohsiung, Taiwan.
  • 3 Department of Medical Science and Biotechnology, I-Shou University, 82445 Kaohsiung, Taiwan.
  • 4 Department of Pathology, E-Da Hospital, 82445 Kaohsiung, Taiwan.
  • 5 Department of Physical Therapy, I-Shou University, 82445 Kaohsiung, Taiwan.
  • 6 Department of Occupational therapy, I-Shou University, 82445 Kaohsiung, Taiwan.
  • 7 School of Medicine, I-Shou University, 82445 Kaohsiung, Taiwan.
PMID: 41504053 DOI: 10.31083/FBL45389
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.

Keywords

SB431542; breast cancer; doxorubicin; drug interactions; mutation; p63; tumor suppressor protein p53.

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