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Hedgehog pathway is a regulator of stemness in HER2-positive trastuzumab-resistant breast cancer

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Tam Metin / Full Text (1.558Mb)

Erişim

info:eu-repo/semantics/openAccess

Tarih

2024

Yazar

Er, İdris
Boz Er, Asiye Büşra

Üst veri

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Künye

Er, I., & Boz Er, A. B. (2024). Hedgehog Pathway Is a Regulator of Stemness in HER2-Positive Trastuzumab-Resistant Breast Cancer. International Journal of Molecular Sciences, 25(22), 12102. https://doi.org/10.3390/ijms252212102

Özet

HER2 overexpression occurs in 20–30% of breast cancers and is associated with poor prognosis. Trastuzumab is a standard treatment for HER2-positive breast cancer; however, resistance develops in approximately 50% of patients within a year. The Hedgehog (Hh) signalling pathway, known for its role in maintaining stemness in various cancers, may contribute to trastuzumab resistance in HER2-positive breast cancer. This study aimed to investigate the role of Hedgehog signalling in maintaining stemness and contributing to trastuzumab resistance in HER2-positive breast cancer cell lines. Trastuzumab-resistant HER2-positive breast cancer cell lines, SKBR3 and HCC1954, were developed through continuous trastuzumab exposure. Cells were treated with GANT61 (Hh inhibitor, IC50:10 µM) or SAG21K (Hh activator, IC50:100 nM) for 24 h to evaluate the Hedgehog signalling response. Stemness marker expression (Nanog, Sox2, Bmi1, Oct4) was measured using qRT-PCR. The combination index (CI) of GANT61 with trastuzumab was calculated using CompuSyn software (version 1.0) to identify synergistic doses (CI < 1). The synergistic concentrations’ impact on stemness markers was assessed. Data were analysed using two-way ANOVA and Tukey’s post hoc test (p < 0.05). Trastuzumab-resistant cells exhibited increased Hedgehog signalling activity. Treatment with GANT61 significantly downregulated stemness marker expression, while SAG21K treatment led to their upregulation in both SKBR3-R and HCC1954-R cells. The combination of GANT61 and trastuzumab demonstrated a synergistic effect, markedly reducing the expression of stemness markers. These findings indicate that Hedgehog signalling plays a pivotal role in maintaining stemness in trastuzumab-resistant cells, and that the inhibition of this pathway may prevent tumour progression. Hedgehog signalling is crucial in regulating stemness in trastuzumab-resistant HER2-positive breast cancer. Targeting this pathway could overcome resistance and enhance trastuzumab efficacy. Further studies should explore the clinical potential of Hedgehog inhibitors in combination therapies.

Kaynak

International Journal of Molecular Sciences

Cilt

25

Sayı

22

Bağlantı

https://doi.org/10.3390/ijms252212102
https://hdl.handle.net/11436/9819

Koleksiyonlar

  • PubMed İndeksli Yayınlar Koleksiyonu [2443]
  • Scopus İndeksli Yayınlar Koleksiyonu [5931]
  • TF, Temel Tıp Bilimleri Bölümü Koleksiyonu [691]
  • WoS İndeksli Yayınlar Koleksiyonu [5260]



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