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Keap1-Nrf2 Pathway Regulates ALDH and Contributes to Radioresistance in Breast Cancer Stem Cells

Dinisha Kamble1, Megharani Mahajan1, Rohini Dhat1

  • 1Redox Biology Lab, National Centre for Cell Science (NCCS), Pune 411007, India.

Cells
|January 9, 2021
PubMed

Insights

Breast cancer stem cells (BCSCs) resist radiotherapy via the Nrf2-Keap1 pathway. Targeting these ALDH+ BCSCs with miR200a may improve treatment outcomes by reducing radioresistance.

Area of Science:

  • Oncology
  • Cancer Stem Cell Biology
  • Radiotherapy Resistance

Background:

  • Tumor recurrence post-radiotherapy is often linked to breast cancer stem cells (BCSCs).
  • The mechanisms driving BCSC radioresistance, particularly the Nrf2-Keap1-Bach1 pathway, are not fully understood.
  • Low reactive oxygen species (ROS) and high antioxidant capacity are implicated in radioresistance.

Purpose of the Study:

  • To investigate the role of the Nrf2-Keap1 signaling pathway in the radioresistance of breast cancer stem cells (BCSCs).
  • To elucidate the mechanisms by which fractionated radiation affects BCSCs and their radioresistance.
  • To explore the potential of targeting BCSCs via miR200a for overcoming radioresistance.

Main Methods:

  • Fractionated radiotherapy was administered to BCSCs.
  • Flow cytometry and sphere formation assays were used to assess ALDH+ population and stem cell characteristics.
  • Western blotting and quantitative PCR were employed to analyze protein and gene expression, including Nrf2, Keap1, and miR200a.
  • Nrf2 knockdown and tumor xenograft models in immunocompromised mice were utilized to evaluate tumorigenic potential and radioresistance.

Main Results:

  • Fractionated radiation increased the ALDH+ subpopulation, enhanced sphere formation, promoted epithelial-to-mesenchymal transition (EMT), and boosted BCSC radioresistance.
  • Radiation activated Nrf2 signaling through Keap1 silencing, increasing BCSC tumor-initiating capacity.
  • Nrf2 knockdown reduced the ALDH+ population, stem cell markers, and radioresistance, while blocking tumor formation in vivo.
  • miR200a expression increased, suggesting a role in Keap1 silencing, independent of promoter methylation changes in Keap1 or GSK-3β.

Conclusions:

  • The ALDH+ BCSC population contributes significantly to breast tumor radioresistance via the Nrf2-Keap1 pathway.
  • Nrf2-Keap1 signaling regulates mesenchymal-epithelial plasticity, tumor-initiating ability, and radioresistance in BCSCs.
  • Targeting BCSCs with miR200a presents a potential therapeutic strategy, though further investigation is required.
Keywords:
ALDH activityBCSCKeap1Nrf2ROSepithelial–mesenchymal transition (EMT)fractionated dose of γ radiationmiR200aradioresistance

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