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

Tamoxifen remains the standard treatment for estrogen receptor alpha (ER α) positive breast cancer (BC) cases. However, a significant proportion of patients develop chemoresistance, leading to disease recurrence. The Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), coded by NFE2L2 gene, has emerged as a key player in chemoresistance and tumoral progression across multiple cancer types, including BC. This study aimed to analyze the role of Nrf2 in metastasis-related processes in a tamoxifen-metabolite-resistant BC cell variant (MCF-7Var-H) and to assess the impact of Nrf2 modulation. We analyzed Nrf2 expression and nuclear localization and observed that both were increased in endocrine-chemoresistant MCF-7Var-H cells compared with MCF-7 parental cells. Critically, we assessed the effects of Nrf2 on migration, invasion, and metalloproteinase secretion capacity using wound-healing assays, Boyden chamber assays, and zymography, respectively. Our results suggest that Nrf2 actively promotes metastatic behaviors in the resistant variant. To further explore its pharmacological relevance, we designed and synthesized small interfering RNAs (siRNAs) targeting NFE2L2 mRNA in its coding region by heterogeneous-phase chemical synthesis. Transfection with these siRNAs significantly inhibited metastasis-related functions such as migration in MCF-7Var-H cells. Overall, siRNAs targeting Nrf2 may be promising tools for treating chemoresistant and metastatic breast cancer.