The genomic signature of breast cancer prevention

Abstract

The breast of parous postmenopausal women exhibits a specific signature that has been induced by a full term pregnancy. This signature is centered in chromatin remodeling and the epigenetic changes induced by methylation of specific genes which are important regulatory pathways induced by pregnancy. Through the analysis of the genes found to be differentially methylated between women of varying parity, multiple positions at which beta-catenin production and use is inhibited were recognized. The biological importance of the pathways identified in this specific population cannot be sufficiently emphasized because they could represent a safeguard mechanism mediating the protection of the breast conferred by full term pregnancy.

Figure 1

Overview of how the DNA methylation levels appear in the Integrative Genomics Viewer (IGV). At the top of the figure is the ideogram of the chromosome given by IGV, with the area currently being examined marked in red. At the bottom is the overall shape of the gene containing exons and introns. Exons are shown as thicker blue sections on the overall gene. The gray bars represent the methylation levels of each volunteer at each base pair. They are created by combining each read resulting from the sequencing done on the samples. The higher they are, the higher the percentage of methylation is at any given base pair. When there was an area of higher methylation occurring in at least four of the members of one parity group as compared to all members of the opposing group, that area was defined as a differentially methylated region (DMR).

Figure 2

DMRs for PRKAR2B. At the top we see the gene shape, with the red marked DMRs. Any colored locations within the gray bars indicate a nucleotide read which is different from the reference genome.

Figure 3

Canonical WNT/β-catenin signaling genes marked in green are hypermethylated in parous women (suggesting down-regulation of the gene in parous women). Genes in red are hypermethylated within nulliparous women. Genes marked with (*) were observed differentially expressed the microarray data. This canonical pathway was generated through the use of IPA (Ingenuity^® Systems) [43].

Figure 4

Interaction of target genes in Wnt/β-catenin signaling. The green genes are statistically parous hypermethylated, while the ones colored red are statistically nulliparous hypermethylated. The darker genes have recorded DMRs, and this is to the exception of GSK3B, which was first found statistically significant hypermethylated in the parous breast, but its DMR is hypermethylated in the nulliparous samples. This network was generated through the use of IPA (Ingenuity^® Systems) [43].