Estrogen Receptor (ER) β or p53 Attenuates ERα-mediated Transcriptional Activation on the BRCA2 Promoter

Abstract

BRCA2 is closely related to the pathogenesis of breast cancer. In the present study, we found that estrogen can activate BRCA2 transcription, which is estrogen receptor (ER) ␣-dependent. During estrogen treatment, ER␣ interacted with CREB-binding protein/p300, p68/p72, and MyoD and formed an activating transcriptional complex that could bind to many Sp1 sites on the BRCA2 promoter and activate its transcription by inducing histone acetylations. MyoD is a new component of ER␣ complex. ER␤ or p53 attenuated ER␣-mediated transcriptional activation by preventing the recruitment of ER␣ transcriptional complex and histone acetylations on the BRCA2 promoter. ER␤ interacted with ER␣ and CREB-binding protein/p300 and formed a weak activating transcriptional complex that competed for binding to Sp1 sites with ER␣ transcriptional complex and slightly attenuated BRCA2 transcription. Different from ER␤, p53 interacted with HDAC1 and CtBP1 and formed an inhibiting transcriptional complex that could compete for binding to Sp1 sites with ER␣ transcriptional complex and inhibit BRCA2 transcription more significantly.Breast cancer is the second leading cause of death in American women, accounting for more than 50,000 deaths each year. The breast cancer and ovarian susceptibility genes 1 and 2 (BRCA1 and BRCA2) 3 were identified based on their genetic linkage to familial early onset of breast and ovarian cancer syndromes (1-3). Mutations in the BRCA1 and BRCA2 are characterized by predisposition to familial breast and ovarian cancer. However, reduced levels of wild-type BRCA1 and BRCA2 expression have been detected in a large percentage of sporadic breast tumors in the absence of BRCA1 and BRCA2 mutations (4 -6), suggesting that defects in transcriptional regulation of the BRCA1 and BRCA2 genes contribute to sporadic breast and ovarian tumorigenesis (7,8). Detection of this transcriptional regulation in cancer cells may provide a molecular mechanistic basis for sporadic breast and ovarian tumor formation.In addition to attenuation of BRCA1 and BRCA2 expression by mutation or promoter hypermethylation, BRCA1 and BRCA2 expression are also controlled by transcriptional factors (9). There are only a few studies about the promoter transcription of BRCA2. Nuclear factor-B can activate the BRCA2 promoter activity (10); p53 represses the BRCA2 promoter activity and down-regulates BRCA2 mRNA and protein levels in response to DNA damage (11). So far, there is no report on how estrogen receptor (ER) ␣ activates BRCA2 transcription during E 2 treatment and how ER␤ or p53 attenuate the BRCA2 transcription by competing with ER␣ transcriptional complex for binding to Sp1 sites on the BRCA2 promoter region upstream of the transcription start site. In this study, we investigated changes in these complexes on the BRCA2 promoter region and their effects on BRCA2 transcription. EXPERIMENTAL PROCEDURESCell Lines, Culture, Plasmids, and Transfection-Human breast cancer cell lines MDA-MB-231 and MCF-7 were maintained in RPMI 1640 medium containing 10% f...

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