Differential methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry

Abstract

Aggressive high-grade, estrogen receptor negative (ER-) breast cancer is more common among American women of African ancestry (AA) than those of European ancestry (EA). Epigenetic mechanisms, particularly DNA methylation and altered microRNA (miRNA) expression, may contribute to racial differences in breast cancer. However, few studies have specifically characterized genome-wide DNA methylation-based modifications at the miRNA level in relation to ER+ and ER- subtype, and their functional role in the regulation of miRNA expression, especially among high risk AA women. In this study, we evaluated DNA methylation patterns of miRNA encoding genes and their effect on expression in breast tumors from both AA and EA women. The genome-wide methylation screen identified a total of 7,191 unique CpGs mapped to 1,292 miRNA genes, corresponding to 2,035 unique mature miRNAs. We identified differentially methylated loci (DMLs: (|delta β|)>0.10, FDR<0.05) between ER- and ER+ tumor subtypes, including 290 DMLs shared in both races, 317 and 136 were specific to AA and EA women, respectively. Integrated analysis identified certain DMLs whose methylation levels were significantly correlated with the expression of relevant miRNAs, such as multiple CpGs within miR-190b and miR-135b highly negatively correlated with their expression. These results were then validated in the TCGA dataset. Target prediction and pathway analysis showed that these DNA methylation-dysregulated miRNAs are involved in multiple cancer-related pathways, including cell cycle G1-S growth factor regulation, cytoskeleton remodeling, angiogenesis, EMT, and ESR1-mediated signaling pathways. In summary, our results suggest that DNA methylation changes within miRNA genes are associated with altered miRNA expression, which may contribute to the network of subtype- and race-related tumor biological differences in breast cancer. These findings support the involvement of epigenetic regulation of miRNA expression and provide insights into the relations of clinical-relevant miRNAs to their target genes, which may serve as potential preventative and therapeutic targets.

Aberrant promoter hypermethylation of miR-335 and miR-145 is involved in breast cancer PD-L1 overexpression

“…In BC, several miRs undergo transcriptional inactivation by hypermethylation of their promoters. This can lead to the overactivity of their oncogenic targets 48 . CpG island hypermethylation-mediated silencing of miR-34b/c, miR-148, and miR-9-3 is correlated with the loss of oncogenic target gene regulation, such as C-MYC, E2F3, CDK6, and TGIF2, and promotes invasion and metastasis 49 .…”

Aberrant promoter hypermethylation of miR-335 and miR-145 is involved in breast cancer PD-L1 overexpression

“…In BC, several miRs undergo transcriptional inactivation by hyper methylation of their promoters. This can lead to the overactivity of their oncogenic targets 47 . CpG island hyper methylation-mediated silencing of miR-34b/c, miR-148, and miR-9-3 is correlated with the loss of oncogenic target gene regulation, such as C-MYC, E2F3, CDK6, and TGIF2, and promotes invasion and metastasis.…”

Crosstalk between Methylation and ncRNAs in Breast Cancer: Therapeutic and Diagnostic Implications

“…Notably, Poli et al revealed that the methylation level of basal BC cells is higher than luminal subtype cells, and the miR-29c expression is negatively relevant to the methylation status, which indicates that the differential methylation pattern drives the subtype-specific expression of miRNA [ 48 ]. Interestingly, Gong et al evaluated the DNA methylation patterns of BC subtype-related miRNAs among American women of African ancestry and European ancestry and found differential methylation sites for lineages, suggesting that the DNA methylation patterns of miRNAs are not only subtype-specific but also lineage-specific [ 69 ]. In addition, circadian rhythm disturbances and xenoestrogen exposure may transform the DNA methylation pattern of miRNA and lead to epigenetic genetic alterations in BC [ 70 , 71 , 72 ].…”