INVESTIGATING THE ROLE OF NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) IN BREAST CANCER CELL-STATE DYNAMICS

Abstract

Tumour heterogeneity describes the existence of malignant cells exhibiting distinct functional states within a tumour. Accumulating evidence suggest that interconversions can occur between cellular states. Understanding the signals driving these transitions will be crucial for development of effective treatments against the disease. Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) is a transcription factor that functions as a master regulator of antioxidant and cytoprotective responses. Given its pivotal role in tumour progression, we hypothesised that Nrf2 may be involved in governing breast cancer cell-state dynamics. A protocol was developed for prolonged siRNA-mediated silencing of Nrf2 in MCF10CA1h. Perturbations in cell-state equilibrium were observed; siNrf2-transfected cells switched from a pre-dominantly CD24-/EpCAM-/low to a CD24+/EpCAMmed/high phenotype. Expression of a mixed epithelial (E) /mesenchymal (M) signature, concomitant with increased stem-like traits and enhanced migratory capacity resembled transition to an intermediate E/M state. Our preliminary findings indicate potential involvement of Nrf2 in maintaining cell-state equilibrium.