RelB Silencing Reverse Tamoxifen Resistance Of Breast Cancer Cells By Elevating ROS Levels

Breast cancer is the most commonly diagnosed malignant tumor among women worldwild,and endocrine adjuvant therapy is one of the major treatments.However,acquired resistance of endocrine drugs limits the effectiveness of clinical treatment,and the mechanism of resistance remains unclear.Aberrant activation of NF-?B signaling is frequently found in triple-negative basal-like breast cancer cells,but the cause of this activation has remained elusive.The five subunits of the NF-?B transcription factor family,RelA(p65),RelB,cRel,NF-?B1(p50 and its precursor p105)and NF-?B2(p52 and its precursor p100),form homodimers or heterodimers.It has been reported that the expression level of RelB gene is negatively correlated with estrogen receptor targeted by Tamoxifen(Tam)in breast cancer.In this study,we show the expression of RelB was remarkable increased in resistant cell line MCF-7/TamR compared with wild type MCF-7.Down-regulation of RelB based on a CRISPR/Cas9 system remarkably sensitized resistance breast cancer cells to Tamoxifen(Tam),while overexpression of RelB significantly increased resistance to Tam in breast cancer cells.The mitochondrial function was enhanced and the increased ROS level was inhibited in drug-resistant cells after Tam administration.After transfecting ROS inhibitor,the sensitivity of Tam was increased in drug resistant cells.Our study confirmed that RelB inhibited oxidative stress through MnSOD expression enhancement,which led to insensitivity of breast cancer cells to tamoxifen in vivo and in vitro.Overall,we found that NF-?B transcription factor RelB is a key factor in mediating the sensitivity of tamoxifen in breast cancer cells.This study may provide a potential target for endocrine therapy and offer new ideas for the mechanism study of endocrine therapy resistance in breast cancer.