Functional Impact of Sequence Alterations Found in BRCA1 Promoter/5'UTR Region in Breast/Ovarian Cancer Families from Upper Silesia, Poland

The human BRCA1 gene is under the transcriptional control of two different promoters, α and β that drive the transcription of exon 1a and 1b, respectively [22]. At the RNA level each of the alternative first exons is linked by splicing with exon 2 [21]. However, the translational initiation site is the same for the two mRNA variants and is located in exon 2 [11]. The BRCA1 5'UTR region coded by exon 1b contains three additional ATG codons upstream of the major translation initiation site [21]. The promoter α is bidirectional and shared with the NBR2 gene [4,21]. BRCA1 contains multiple transcription factor binding sites identified in 5' flanking regions of exon 1a and exon 1b [17,18]. The different transcripts of the BRCA1 gene are present at different levels in various normal and tumour tissues and may have distinct biological functions [21]. Expression of transcripts α and β of the BRCA1 gene may be co-regulated by use of a dual promoter system. Moreover, the two mRNAs may differ in their stability or translational efficiency [21].Germline mutations within the BRCA1 gene are responsible for familial cancer and reduced expression of the BRCA1 gene is frequently observed in sporadic breast [12,16,20] and ovarian tumours [23]. Various mechanisms such as methylation of the CpG islands within the promoter region [2,6,10,13], allelic deletion of the BRCA1 locus and sequence alterations identified outside the BRCA1 coding region, especially within the positive regulatory region (PRR) of the BRCA1 promoter, can modulate the level of BRCA1 expression [17,19]. There are also other mechanisms responsible for breast and ovarian cancer pathogenesis [5,15]. Expression patterns of BRCA1 mRNAs and differences in their translatability [14] and disruption of the DNA-protein complexes [18] may also contribute to breast/ovarian cancer susceptibility.Our aim was to investigate the functional effect of sequence alterations within the BRCA1 promoter/5'UTR region using luciferase reporte