Regulation of BRCA1 expression and its relationship to sporadic breast cancer

Abstract

Germ-line mutations in the BRCA1 tumour suppressor gene contribute to familial breast tumour formation, but there is no evidence for direct mutation of the BRCA1 gene in the sporadic form of the disease. In contrast, decreased expression of the BRCA1 gene has been shown to be common in sporadic tumours, and the magnitude of the decrease correlates with disease progression. BRCA1 expression is also tightly regulated during normal breast development. Determining how these developmental regulators of BRCA1 expression are co-opted during breast tumourigenesis could lead to a better understanding of sporadic breast cancer aetiology and the generation of novel therapeutic strategies aimed at preventing sporadic breast tumour progression.

Figure 1

Potential mechanisms for the reducing BRCA1 expression. Schematics of the two BRCA1 alleles are shown. (a) Endo-reduplication of a methylated allele would lead to complete loss of expression. (b) Expression from only one allele could be indicative of methylation of one of the promoters. (c) Methylation of both promoters through an unidentified mechanism would lead to a dramatic decrease in expression. (d) Increased NBR2 expression could lead to decreased BRCA1 expression. (e) p53 could inhibit factors such as E2F. (f) Loss of DNA binding by the GABP-α/β complex leads to decreased expression. (g) ID4 expression leads to the down regulation of the BRCA1 promoter, presumably through interaction with a transcription factor that normally regulates the promoter. (h) BRCA1 and ID4 levels appear to be coregulated.

Figure 2

The structure of the human and mouse BRCA1 loci are shown. Transcription initiation sites are indicated by arrows. The general exon structure is indicated by the variously shaded boxes. The patterned box indicates the location of an acidic ribosomal phosphoprotein P1 pseudocopy [34], which appears to have been inserted into the region between NBR1 and the BRCA1 pseudo-gene. The BRCA1 gene appears to have two alternative first exons, although the 1A exon appears to be used much more frequently.

Figure 3

The sequence of the promoter region between the NBR2 and the BRCA1 genes is indicated. The transcriptional start sites are indicated by the left and right pointing arrows for the respective genes. Binding sites for transcription factors identified as being important for promoter activity are boxed. The minimal bidirectional promoter [40] is indicated by the dashed line. The first exon of the BRCA1 gene is indicated by the shaded box. CpG dinucleotides that are potentially methylated are shown in red. The location of an EcoRI and Sac I are indicated by thick lines.

Figure 4

Brca1 expression in the mouse mammary gland. The line represents relative brca1 expression levels and is regulated in periodic waves during mammary gland development. Levels are low in the quiescent periods before puberty, in the virgin adult gland and in the resting gland. Levels are also low during lactational terminal differentiation. Levels are high during the proliferative periods at puberty and during pregnancy. Levels are also high during the apoptotic period of involution after weaning.