A Comparative Analysis of Genetic and Epigenetic Events of Breast and Ovarian Cancer Related to Tumorigenesis

Abstract

Breast cancer persists as the most common cause of cancer death in women worldwide. Ovarian cancer is also a significant source of morbidity and mortality, as the fifth leading cause of cancer death among women. This reflects the continued need for further understanding and innovation in cancer treatment. Though breast and ovarian cancer usually present as distinct clinical entities, the recent explosion of large-scale -omics research has uncovered many overlaps, particularly with respect to genetic and epigenetic alterations. We compared genetic, microenvironmental, stromal, and epigenetic changes common between breast and ovarian cancer cells, as well as the clinical relevance of these changes. Some of the most striking commonalities include genetic alterations of BRCA1 and 2, TP53, RB1, NF1, FAT3, MYC, PTEN, and PIK3CA; down regulation of miRNAs 9, 100, 125a, 125b, and 214; and epigenetic alterations such as H3K27me3, H3K9me2, H3K9me3, H4K20me3, and H3K4me. These parallels suggest shared features of pathogenesis. Furthermore, preliminary evidence suggests a shared epigenetic mechanism of oncogenesis. These similarities, warrant further investigation in order to ultimately inform development of more effective chemotherapeutics, as well as strategies to circumvent drug resistance.

Keywords: breast cancer; epigenetics; ovarian cancer.

Figure 1

Mutated genes in breast and ovarian cancer. Bolded genes are those significantly mutated in breast and ovarian cancer. Red lines show inhibition of expression; solid black lines show induction of expression; dashed black lines show effector events.

Figure 2

Pathways regulated by miR-100 (A), miR-9 (B), and miR-233 (C). Red lines show inhibition; dashed black lines show effector events.

Figure 3

Model of DNA methylation and histone methylation regulating gene expression for breast and ovarian cancer initiation. (A,B) Hypermethylation is indicated by red balls (CpG residue). White balls represent unmethylated CpG residues. DNMT1 represents DNA methyl transferase 1, POLII represents RNA polymares II; (B) In the absence of hypermethylation, POLII is able to bind to the promoter region and initiate transcription; (C,D) White balls represent unmethylated, and red balls represent hypermethylated CpG residues. CCCTC is CTCF binding motif. The green circle represents effective insulation zone. Break of insulated zone is shown by dotted green circle.