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Radiotherapy resistance driven by Asparagine endopeptidase through ATR pathway modulation in breast cancer

  • 0Centro Andaluz de Biología Molecular y Medicina Regenerativa - CABIMER, Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Sevilla, Universidad Pablo de Olavide, Américo Vespucio 24, Seville, 41092, Spain.
Journal of Experimental & Clinical Cancer Research : Cr +

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February 26, 2025

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February 26, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Asparagine endopeptidase (AEP) promotes cancer cell survival by maintaining genomic stability and radiotherapy resistance. Inhibiting AEP may sensitize tumors to chemotherapy and serve as a predictive biomarker for treatment selection.

Area Of Science

  • Oncology
  • Molecular Biology
  • Genomics

Background

  • Tumor resistance is a significant challenge in cancer treatment.
  • Asparagine endopeptidase (AEP) overexpression is linked to poor prognosis in solid tumors.
  • Mechanisms connecting AEP to reduced survival in cancer patients are not fully understood.

Purpose Of The Study

  • To identify novel AEP targets and elucidate its role in cancer.
  • To investigate the link between AEP, genomic stability, and resistance to radiotherapy in breast cancer.
  • To evaluate the AEP/ATR axis as a predictive biomarker and therapeutic target.

Main Methods

  • Utilized high-throughput proteomics, cellular and molecular biology techniques, and clinical breast cancer data.
  • Employed immunoblotting, qPCR, flow cytometry, confocal microscopy, and DNA repair assays.
  • Conducted in-silico analyses (TCGA dataset) and immunofluorescence assays on patient cohorts.

Main Results

  • AEP suppresses ATR and PPP1R10, impacting genomic stability and radiotherapy resistance in breast cancer.
  • Reduced ATR/PPP1R10 levels correlate with worse prognosis in breast cancer patients.
  • AEP inhibition sensitized breast cancer cells to chemotherapy and identified the AEP/ATR axis as a predictive biomarker for radioresistant patients.

Conclusions

  • The AEP/ATR/PPP1R10 axis plays a critical role in breast cancer's genomic stability and radiotherapy resistance.
  • This study reveals new insights into tumor resistance mechanisms.
  • The AEP/ATR axis is validated as a promising predictive biomarker and therapeutic target for radioresistant breast cancer.

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