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Nrf2 Is Associated with Metastasis-Related Processes in a Chemoresistant Breast Cancer Model: Insights from siRNA

Andrea Muñoz-Ayala1,2, Nicolás Serafín-Higuera3,4, Ana Gabriela Leija-Montoya4,5

  • 1Facultad de Medicina y Nutrición Mexicali, Universidad Autónoma de Baja California, Humberto Torres Sanginés S/N, Centro Cívico, Mexicali 21000, BC, Mexico.

International Journal of Molecular Sciences
|May 27, 2026
PubMed

Insights

Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) drives chemoresistance and metastasis in breast cancer. Inhibiting Nrf2 with small interfering RNAs (siRNAs) shows promise for treating resistant and metastatic breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Estrogen receptor alpha (ER α) positive breast cancer (BC) is typically treated with tamoxifen.
  • Chemoresistance and disease recurrence are significant challenges in BC treatment.
  • Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) is implicated in chemoresistance and tumor progression in various cancers, including BC.

Purpose of the Study:

  • To investigate the role of Nrf2 in metastasis-related processes in tamoxifen-resistant BC cells (MCF-7Var-H).
  • To evaluate the impact of modulating Nrf2 expression on metastatic behaviors.
  • To explore the therapeutic potential of targeting Nrf2 in chemoresistant and metastatic BC.

Main Methods:

  • Analysis of Nrf2 expression and nuclear localization in MCF-7Var-H cells compared to parental MCF-7 cells.
  • Assessment of cell migration, invasion, and metalloproteinase secretion using wound-healing, Boyden chamber assays, and zymography.
  • Design and synthesis of small interfering RNAs (siRNAs) targeting NFE2L2 mRNA for Nrf2 inhibition.

Main Results:

  • Nrf2 expression and nuclear localization were elevated in endocrine-chemoresistant MCF-7Var-H cells.
  • Nrf2 was found to promote migration, invasion, and metalloproteinase secretion, indicating active promotion of metastatic behaviors.
  • siRNA-mediated inhibition of Nrf2 significantly reduced metastasis-related functions, including migration, in MCF-7Var-H cells.

Conclusions:

  • Nrf2 plays a crucial role in promoting metastatic behaviors in tamoxifen-resistant breast cancer.
  • Targeting Nrf2 using siRNAs represents a potential therapeutic strategy for chemoresistant and metastatic breast cancer.
  • Nrf2 inhibition may offer a novel approach to overcome treatment resistance and prevent metastasis in breast cancer patients.
Keywords:
Nrf2breast cancerchemoresistancemetastasistamoxifen

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