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<p>The resistance of human epidermal growth factor receptor 2 (HER2)–positive breast cancer (BC) patients to trastuzumab (Tmab) severely restricts its efficacy. As a natural metabolite with antitumor activity, whether cycloastragenol (CAG) can overcome Tmab resistance and its related mechanism are not clear. This study aims to verify if CAG reverses Tmab resistance in HER2-positive breast cancer cells, clarify its regulatory effects on resistant cell behaviors, and explore the role of the EZH2/PTEN/AKT axis. The study design is combined in vivo and in vitro study. The BT474-TR cells were constructed, and HER2 expression was detected by Western blot and immunofluorescence. Cell Counting Kit-8 assay served to screen the optimal CAG concentration and Tmab dosage. Cell proliferation, migration, and invasion capabilities were evaluated via CFSE staining, colony formation assay, and Transwell and scratch assays. Flow cytometry was employed to examine apoptosis and cell cycle arrest. A xenograft tumor model was established in nude mice. Pathological changes were observed via HE staining, apoptosis was detected using TUNEL staining, microvascular density and VEGF levels were assessed by immunohistochemistry, and protein expression was validated by Western blot. Tmab reduced BT474-TS cell viability and downregulated HER2, while exhibiting minimal effects on HER2-high expression BT474-TR and JIMT-1 cells. CAG treatment enhanced the efficacy of Tmab against drug-resistant cells, reducing cell viability and proliferation, promoting apoptosis, and inducing G0/G1 phase cycle arrest. CAG suppressed migration and invasion capabilities while reversing the EMT phenotype. Additionally, CAG downregulated EZH2 and p-AKT while upregulating PTEN; overexpression EZH2 diminished CAG’s antitumor activity. Following CAG combined with Tmab treatment, tumor volume and weight in nude mice were smaller, and tumor tissue exhibited increased pathological damage, elevated apoptotic cells, and reduced microvascular density and VEGF levels. CAG modulates the cell cycle and EMT through the EZH2/PTEN/AKT pathway, effectively overcoming Tmab resistance in HER2-positive BC cells. Clinical trial number: Not applicable.</p>

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Cycloastragenol overcomes trastuzumab resistance in HER2-positive breast cancer by regulating cell cycle and epithelial-mesenchymal transition through EZH2/PTEN/AKT pathway

  • 期刊论文

  • 发表日期：

    2026年7月27日

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  • Mingyuan Wu,
  • Fenggang Hou,
  • Zhaoshuo Yang,
  • Zhenfeng Zhu,
  • Yao Wang,
  • Hong Wang

摘要

The resistance of human epidermal growth factor receptor 2 (HER2)–positive breast cancer (BC) patients to trastuzumab (Tmab) severely restricts its efficacy. As a natural metabolite with antitumor activity, whether cycloastragenol (CAG) can overcome Tmab resistance and its related mechanism are not clear. This study aims to verify if CAG reverses Tmab resistance in HER2-positive breast cancer cells, clarify its regulatory effects on resistant cell behaviors, and explore the role of the EZH2/PTEN/AKT axis. The study design is combined in vivo and in vitro study. The BT474-TR cells were constructed, and HER2 expression was detected by Western blot and immunofluorescence. Cell Counting Kit-8 assay served to screen the optimal CAG concentration and Tmab dosage. Cell proliferation, migration, and invasion capabilities were evaluated via CFSE staining, colony formation assay, and Transwell and scratch assays. Flow cytometry was employed to examine apoptosis and cell cycle arrest. A xenograft tumor model was established in nude mice. Pathological changes were observed via HE staining, apoptosis was detected using TUNEL staining, microvascular density and VEGF levels were assessed by immunohistochemistry, and protein expression was validated by Western blot. Tmab reduced BT474-TS cell viability and downregulated HER2, while exhibiting minimal effects on HER2-high expression BT474-TR and JIMT-1 cells. CAG treatment enhanced the efficacy of Tmab against drug-resistant cells, reducing cell viability and proliferation, promoting apoptosis, and inducing G0/G1 phase cycle arrest. CAG suppressed migration and invasion capabilities while reversing the EMT phenotype. Additionally, CAG downregulated EZH2 and p-AKT while upregulating PTEN; overexpression EZH2 diminished CAG’s antitumor activity. Following CAG combined with Tmab treatment, tumor volume and weight in nude mice were smaller, and tumor tissue exhibited increased pathological damage, elevated apoptotic cells, and reduced microvascular density and VEGF levels. CAG modulates the cell cycle and EMT through the EZH2/PTEN/AKT pathway, effectively overcoming Tmab resistance in HER2-positive BC cells. Clinical trial number: Not applicable.