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Background <p>Breast cancer (BC) is the most frequently diagnosed cancer among women and the leading cause of cancer-related mortality globally. One of the current systemic therapies against estrogen receptor-positive BC is hormonal therapy with tamoxifen (TAM), a selective estrogen receptor modulator. Recent studies showed that TAM resistance may occur often due to enhanced drug efflux mediated by ATP-binding cassette (ABC) transporters and ultimately can affect treatment efficacy. Epibrassinolide (EBR) is an apoptotic agent by inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Continuous activation of UPR was suggested as a strategy to combat drug resistance, underscoring its potential as a therapeutic target.</p> Methods and results <p>In this study, we showed the anti-cancer potential of EBR on TAM-resistant cells, as well as parental cells by MTT cell viability, clonogenic and hanging drop assays, lactate dehydrogenase (LDH) cytotoxicity assay, and fluorescence stainings using 4’6-diamidino-2-phenylindole (DAPI) and 3,3’-Dihexyloxacarbocyanine Iodide (DiOC6) for DNA condensation and mitochondrial membrane potential loss, respectively. The apoptotic potential of combined treatment of EBR and TAM was evaluated by western blotting and flow cytometry. The contribution of EBR-induced endoplasmic reticulum stress to the attenuation of TAM resistance was substantiated by its reversal upon pharmacological inhibition with TUDCA (Tauroursodeoxycholic acid).</p> Conclusions <p>Collectively, our findings demonstrated that EBR exerts potent anti-cancer effects on both TAM-resistant and parental breast cancer cells. The combined administration of EBR and TAM enhanced apoptotic signaling. Our data also revealed that EBR-induced endoplasmic reticulum stress plays a critical role in sensitizing TAM-resistant cells, since pharmacological inhibition of ER stress with TUDCA markedly attenuated these effects. Taken together, these results highlight EBR as a promising adjuvant strategy to overcome TAM resistance by targeting ER stress–mediated apoptotic pathways.</p>

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Combination treatment with epibrassinolide overcomes tamoxifen resistance in breast cancer cells via endoplasmic reticulum stress induction

  • 期刊论文

  • 发表日期：

    2025年12月19日

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  • Zeynep Demirel,
  • Esranur Kopal,
  • Nilay Dinçkurt,
  • Elif Damla Arisan,
  • Pınar Obakan Yerlikaya

摘要

Background

Breast cancer (BC) is the most frequently diagnosed cancer among women and the leading cause of cancer-related mortality globally. One of the current systemic therapies against estrogen receptor-positive BC is hormonal therapy with tamoxifen (TAM), a selective estrogen receptor modulator. Recent studies showed that TAM resistance may occur often due to enhanced drug efflux mediated by ATP-binding cassette (ABC) transporters and ultimately can affect treatment efficacy. Epibrassinolide (EBR) is an apoptotic agent by inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Continuous activation of UPR was suggested as a strategy to combat drug resistance, underscoring its potential as a therapeutic target.

Methods and results

In this study, we showed the anti-cancer potential of EBR on TAM-resistant cells, as well as parental cells by MTT cell viability, clonogenic and hanging drop assays, lactate dehydrogenase (LDH) cytotoxicity assay, and fluorescence stainings using 4’6-diamidino-2-phenylindole (DAPI) and 3,3’-Dihexyloxacarbocyanine Iodide (DiOC6) for DNA condensation and mitochondrial membrane potential loss, respectively. The apoptotic potential of combined treatment of EBR and TAM was evaluated by western blotting and flow cytometry. The contribution of EBR-induced endoplasmic reticulum stress to the attenuation of TAM resistance was substantiated by its reversal upon pharmacological inhibition with TUDCA (Tauroursodeoxycholic acid).

Conclusions

Collectively, our findings demonstrated that EBR exerts potent anti-cancer effects on both TAM-resistant and parental breast cancer cells. The combined administration of EBR and TAM enhanced apoptotic signaling. Our data also revealed that EBR-induced endoplasmic reticulum stress plays a critical role in sensitizing TAM-resistant cells, since pharmacological inhibition of ER stress with TUDCA markedly attenuated these effects. Taken together, these results highlight EBR as a promising adjuvant strategy to overcome TAM resistance by targeting ER stress–mediated apoptotic pathways.