ERα, ERβ And P53 Modulate Transcriptional Activity Of The BRCA2 Gene

ERα,ERβand p53 modulate transcriptional activity of the BRC A2 geneObjective:To investigate whether or how the transcription factor ERα,ERβand p53 regulate BRCA2 transcription,and evaluate the variation of BRCA2 promoter's DNA sequences in High-risk breast cancer patients.Methods:We transiently transfected ERα,ERβand p53 plasmids into breast cancer cell lines,then performed RT-PCR,Western—blot,CHIP to detect whether they could combine to the BRCA2 promoter,regulate its transcription and affect its protein level.We collected peripheral blood samples from High-risk breast cancer patients,detected the variation of BRCA2 promoter sequences by DHPLC and DNA Sequence Analysis.Results:We find that estrogen can activate BRCA2 transcription,which is ERα-dependent.During estrogen treatment,ERa interacts with CBP/p300 and forms an activating transcriptional complex which can bind to many Spl sites on the BRCA2 promoter and activate its transcription by inducing histone acetylations;ERβinteracts with ERα,CBP/p300 and forms a weak activating transcriptional complex which competes for binding to Spl sites with ERa transcriptional complex and slightly attenuates BRCA2 transcription;Different from ERβ,p53 interacts with HDAC1,CtBPl and CtBP2 forms an inhibiting transcriptional complex which can compete for binding to Spl sites with ERαtranscriptional complex and inhibit BRCA2 transcription.Checking 400 BRCA2 promoter DNA sequences,we found only one mutation 50insl 1 in exonl of BRCA2.Conclusion:In the stimulation of E2,ERαand CBP/P300 can form a transcription complex and bind to BRCA2 promoter,through acetylating the core histone protein,increasing BRCA2 transcription.However,ERβand p53 can attenuate ERα-mediated transcriptional activation on the BRCA2 prmoter.