Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer

摘要: Tamoxifen is widely used as an adjuvant therapy for patients with estrogen receptor (ERα)-positive tumors. However, the clinical benefit often limited because of emergence drug resistance. In this study, overexpression ribonucleotide reductase M2 (RRM2) in MCF-7 breast cancer cells resulted a reduction effectiveness tamoxifen, through downregulation ERα66 and upregulation 36-kDa variant ER (ERα36). We identified that NF-κB, HIF1α, MAPK/JNK are major pathways affected by RRM2 result increased NF-κB activity protein levels EGFR, HER2, IKKs, Bcl-2, RelB, p50. RRM2-overexpressing also exhibited higher migratory invasive properties. Through time-lapse microscopy profiling studies tamoxifen-treated T-47D cells, we have RRM2, along other key proteins, altered during acquired tamoxifen Inhibition using siRRM2 or (RR) inhibitor didox not only eradicated effectively prevented tamoxifen-resistant populations but led to reversal many proteins process Because appears be potent activation, combining treatment cooperatively reverses ER-α alterations inhibits activation. Finally, inhibition reversed vivo tumor growth decreased vitro properties, revealing beneficial effect combination includes delay abrogate