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

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 i...

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Autores principales: Gong, Zhihong, Chen, Jianhong, Wang, Jie, Liu, Song, Ambrosone, Christine B., Higgins, Michael J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009363/
https://www.ncbi.nlm.nih.gov/pubmed/33784351
http://dx.doi.org/10.1371/journal.pone.0249229
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author Gong, Zhihong
Chen, Jianhong
Wang, Jie
Liu, Song
Ambrosone, Christine B.
Higgins, Michael J.
author_facet Gong, Zhihong
Chen, Jianhong
Wang, Jie
Liu, Song
Ambrosone, Christine B.
Higgins, Michael J.
author_sort Gong, Zhihong
collection PubMed
description 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.
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spelling pubmed-80093632021-04-07 Differential methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry Gong, Zhihong Chen, Jianhong Wang, Jie Liu, Song Ambrosone, Christine B. Higgins, Michael J. PLoS One Research Article 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. Public Library of Science 2021-03-30 /pmc/articles/PMC8009363/ /pubmed/33784351 http://dx.doi.org/10.1371/journal.pone.0249229 Text en © 2021 Gong et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Gong, Zhihong
Chen, Jianhong
Wang, Jie
Liu, Song
Ambrosone, Christine B.
Higgins, Michael J.
Differential methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry
title Differential methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry
title_full Differential methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry
title_fullStr Differential methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry
title_full_unstemmed Differential methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry
title_short Differential methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry
title_sort differential methylation and expression patterns of micrornas in relation to breast cancer subtypes among american women of african and european ancestry
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009363/
https://www.ncbi.nlm.nih.gov/pubmed/33784351
http://dx.doi.org/10.1371/journal.pone.0249229
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