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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
Summary
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.
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