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Background <p>Breast cancer remains the second leading cause of cancer-related mortality among women worldwide. Doxorubicin is widely used in breast cancer therapy, however, its clinical efficacy is frequently compromised by the development of drug resistance. Growing evidence suggests that small extracellular vesicles/exosomes are involved in intercellular communication might play a critical role in the horizontal transfer of chemoresistance. In this study, we investigated the contribution of exosomes to the acquisition and propagation of doxorubicin resistance in breast cancer.</p> Methods <p>Cell viability, proliferation and colony formation was evaluated using MTT and crystal violet staining. Exosomes were isolated and comprehensively characterized by Scanning electron microscopy (SEM), Dynamic light scattering (DLS) and Western blotting. Activation of different signalling molecules was assessed by using phosphokinase array and Western blotting. Expression and pathway analysis of different signalling molecules in breast cancer patients was done using online patient datasets and bioinformatic analysis.</p> Results and conclusion <p>Doxorubicin resistant cells exhibited enhanced cellular proliferation, glucose uptake and increased lactate production. Exosomes of DOX-resistant cells significantly enhanced cell proliferation of DOX-sensitive breast cancer cells and reduced the sensitivity of DOX-sensitive breast cancer cells to doxorubicin. Delineation of molecular mechanisms revealed dysregulation in cellular signals responsible for imparting doxorubicin resistance in doxorubicin sensitive breast cancer cells. Among different cellular signals, AKT and STAT3 emerged as key hub proteins, with phosphorylated AKT playing a dominant role in mediating doxorubicin resistance. Clinical data further supported the association between activated AKT signalling and poor therapeutic response. Importantly, pharmacological inhibition of AKT effectively re-sensitized doxorubicin resistant breast cancer cells to doxorubicin. Collectively, these findings identify exosomal phosphorylated AKT as a critical mediator of doxorubicin resistance and a potential therapeutic target in breast cancer patient’s resistant to doxorubicin.</p>

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Exosomal transfer of p-AKT drives doxorubicin resistance and predicts poor prognosis in breast cancer

  • 期刊论文

  • 发表日期：

    2026年7月8日

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  • Shazia Gul,
  • Jasmeena Jan,
  • Rumaisa Mohidin,
  • Owais Mohmad Bhat,
  • Abid Hamid Dar,
  • Mohammad Afzal Zargar,
  • Nissar Ahmad Wani

摘要

Background

Breast cancer remains the second leading cause of cancer-related mortality among women worldwide. Doxorubicin is widely used in breast cancer therapy, however, its clinical efficacy is frequently compromised by the development of drug resistance. Growing evidence suggests that small extracellular vesicles/exosomes are involved in intercellular communication might play a critical role in the horizontal transfer of chemoresistance. In this study, we investigated the contribution of exosomes to the acquisition and propagation of doxorubicin resistance in breast cancer.

Methods

Cell viability, proliferation and colony formation was evaluated using MTT and crystal violet staining. Exosomes were isolated and comprehensively characterized by Scanning electron microscopy (SEM), Dynamic light scattering (DLS) and Western blotting. Activation of different signalling molecules was assessed by using phosphokinase array and Western blotting. Expression and pathway analysis of different signalling molecules in breast cancer patients was done using online patient datasets and bioinformatic analysis.

Results and conclusion

Doxorubicin resistant cells exhibited enhanced cellular proliferation, glucose uptake and increased lactate production. Exosomes of DOX-resistant cells significantly enhanced cell proliferation of DOX-sensitive breast cancer cells and reduced the sensitivity of DOX-sensitive breast cancer cells to doxorubicin. Delineation of molecular mechanisms revealed dysregulation in cellular signals responsible for imparting doxorubicin resistance in doxorubicin sensitive breast cancer cells. Among different cellular signals, AKT and STAT3 emerged as key hub proteins, with phosphorylated AKT playing a dominant role in mediating doxorubicin resistance. Clinical data further supported the association between activated AKT signalling and poor therapeutic response. Importantly, pharmacological inhibition of AKT effectively re-sensitized doxorubicin resistant breast cancer cells to doxorubicin. Collectively, these findings identify exosomal phosphorylated AKT as a critical mediator of doxorubicin resistance and a potential therapeutic target in breast cancer patient’s resistant to doxorubicin.