Nrf2is Associated With The Regulation Of Basal Transcriptional Activity Of The BRCA1Gene

Objective:To investigate how the transcription factor Nrf2regulate BRCA1transcription.Methods:Transiently transfecte Nrf2plasmids or siRNA into breast cancer cell lines HCC38、MD-MBA-231and MCF-7, then performe luciferase reporter gene assay to detect BRCA1promoter activity, RT-PCR and Western blot to detect BRCA1mRNA and protein level, and ChIP-reChIP to detect the combining of Nrf2transcriptional complex with BRCA1promoter and histone acetylation of BRCA1promoter, finally perfome immunohistochemical detection ofNrf2and BRCA1in sporadic breast cancer tissues.Results:Luciferase reporter gene assay demonstrates that Nrf2could bind to ARE (Antioxidant response element) site on the BRCA1promoter and active the promoter transcription with the synergism ofCBP and p300. Over-expression ofNrf2in HCC38cells could promote the recruitment of Nrf2transcriptional complex on BRCA1promoter and histone acetylation of BRCA1promoter, therefore stimulate BRCA1expression. And knockdown of Nrf2by siRNA in MCF-7cells could inhibit the the recruitment of Nrf2transcriptional complex on BRCA1promoter and histone acetylation of BRCA1promoter, therefore attenuate BRCA1expression. Treating cells with H2O2could stimulate BRCA1expression by inducing Nrf2and the recruitment of Nrf2complex on BRCA1promoter. The immunohistochemistry of90sporadic breast cancer tissues indicates that Nrf2is associated with BRCA1expression.Conclusion:Overexpression of Nrf2is closely related to the recruitment of an active transcriptional complex on the BRCA1promoter and the histone acetylation of BRCA1promoter in sporadic breast cancer. The decreased expression and abnormal functions of Nrf2may play an important role in the carcinogensis of breast cancer. Nrf2is one of candidate genes associated with cancer susceptibility.