Abstract
IntroductionDecreased transcription of the BRCA1 gene has previously been observed to occur in sporadic breast tumours, making elucidation of the mechanisms regulating the expression of this gene important for our understanding of the etiology of the disease.MethodsTranscriptional elements involved in the regulation of the BRCA1 promoter were analysed by co-transfection experiments into the human MCF-7 and T-47D breast cancer cell lines.ResultsWe have identified a repressor element, referred to as the UP site, within the proximal BRCA1 promoter whose inactivation results in increased promoter activity. An E2F recognition element, previously suggested to mediate repression via E2F-6, is adjacent to the UP site and its inactivation also leads to increased BRCA1 expression. These two elements appear to form a composite repressor element whose combined effect is additive. The UP element is composed of two sequences, one of which binds the ubiquitously expressed ets family transcription factor GABP alpha/beta. This site is distinct from a previously identified GABP alpha/beta site, the RIBS element, though the RIBS site appears to be necessary for derepression of the promoter via mutations in the UP site. Knockdown of GABP alpha using an shRNA vector confirms that this protein is important for the function of both the RIBS and UP sites.ConclusionThe identification of a repressor element in the BRCA1 promoter brings a new level of complexity to the regulation of BRCA1 expression. The elements characterized here may play a normal role in the integration of a variety of signals, including two different growth related pathways, and it is possible that loss of the ability to derepress the BRCA1 promoter during critical periods may contribute to breast transformation.
Highlights
Introduction Decreased transcription of theBRCA1 gene has previously been observed to occur in sporadic breast tumours, making elucidation of the mechanisms regulating the expression of this gene important for our understanding of the etiology of the disease
Knockdown of GABP alpha using an small hairpin RNA (shRNA) vector confirms that this protein is important for the function of both the RIBS and UP sites
The identification of a repressor element in the BRCA1 promoter brings a new level of complexity to the regulation of BRCA1 expression
Summary
Introduction Decreased transcription of theBRCA1 gene has previously been observed to occur in sporadic breast tumours, making elucidation of the mechanisms regulating the expression of this gene important for our understanding of the etiology of the disease. The loss of BRCA1 expression appears to be an important mechanism driving tumour formation in sporadic breast cancer cases [5]. There is evidence to suggest that epigenetic changes and preferential methylation of sites within the BRCA1 promoter region can lead to this down-regulation of expression; collectively, these mechanisms are implicated in only a small percentage of sporadic tumours [6]. These data suggest that transcriptional regulation of the BRCA1 gene may play a major role in the loss of its expression
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