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Dual-specificity phosphatase 8 (DUSP8) induces drug resistance in breast cancer by regulating MAPK pathways

Hanchao Zhang1, Meng Wang1, Di Chen1

  • 1Department of General Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, Beijing, People's Republic of China.

Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research
|April 16, 2022
PubMed

Insights

Dual-specificity phosphatase 8 (DUSP8) is upregulated in drug-resistant breast cancer. Reducing DUSP8 enhances trastuzumab effectiveness by promoting apoptosis and inhibiting cell migration via the MAPK pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Trastuzumab resistance is a major challenge in HER2-positive breast cancer treatment.
  • Dual-specificity phosphatase 8 (DUSP8) has emerged as a potential regulator in cancer progression and drug response.

Purpose of the Study:

  • To investigate the role and molecular mechanism of DUSP8 in trastuzumab resistance in breast cancer.
  • To evaluate DUSP8 as a potential diagnostic marker for trastuzumab response.

Main Methods:

  • Real-time PCR and Western blot for DUSP8 expression analysis.
  • ROC curve analysis for diagnostic value assessment.
  • si-DUSP8 transfection, flow cytometry, MTT, and Transwell assays to study cellular effects.
  • Western blot to analyze MAPK pathway signaling (p-p38, p-ERK).

Main Results:

  • DUSP8 expression was significantly higher in breast cancer tissues/cells and trastuzumab-resistant cells compared to controls.
  • ROC analysis indicated moderate diagnostic value (AUC=0.732, sensitivity=64.86%, specificity=75.76%).
  • DUSP8 knockdown in resistant cells (BT474/TR, SKBR3/TR) promoted apoptosis, reduced cell viability and migration, and decreased trastuzumab resistance.
  • DUSP8 knockdown upregulated p-p38 and p-ERK expression, suggesting MAPK pathway involvement.

Conclusions:

  • DUSP8 is upregulated in trastuzumab-resistant breast cancer and may serve as a diagnostic marker.
  • Knockdown of DUSP8 resensitizes breast cancer cells to trastuzumab by inhibiting proliferation and migration.
  • DUSP8 influences trastuzumab resistance potentially through the modulation of MAPK signaling pathways.
Keywords:
antioxidantsapoptosisbiomarkerscarcinoma

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