Epigenetic changes in BRCA1-mutated familial breast cancer

Abstract

Familial breast cancer occurs in about 10% of breast cancer cases. Germline mutation in BRCA1 is the most penetrant predisposition for the disease. Mutated BRCA1 leads to disease by causing genome instability via multiple mechanisms including epigenetic changes. This review summarizes recent progress in studying the correlation between BRCA1 predisposition and epigenetic alterations in BRCA1-type familial breast cancer.

Keywords: BRCA1; autosomal dominant; epigenetic alteration; familial breast cancer; germline mutation.

Figure 1

BRCA1 and heterochromatin methylation. BRCA1 silences heterochromatin transcription by methylating heterochromatin through interaction with Wip1 phosphatase, HP1, and DNA methyltransferase. BRCA1+ loses heterochromatin demethylation, releases the transcriptional silencing, leads overexpression of heterochromatin transcripts, and causes genome instability. CH3: methyl group.

Figure 2

BRCA1 regulates miR-155 expression. A. BRCA1 maintains intact structure of promoter of miR-155 by suppressing HDAC2 activity, block transcriptional factors binding to promoter elements, resulting in decreased miR-155 transcription; B. Mutated BRCA1 loses its suppression on HDAC2 activity, leading to increased acetylation of miR-155 promoter, increased transcriptional factors binding to promoter elements, and increased miR-155 transcription. The overexpressed miR-155 causes dis-regulation of cytokine signaling pathways, and promotes cellular transformation.