DNA methylation in breast cancers: Differences based on estrogen receptor status and recurrence

Williams, Kristin E.; Jawale, Rahul; Schneider, Sallie S.; Otis, Christopher N.; Pentecost, Brian T.; Arcaro, Kathleen F.

doi:10.1002/jcb.27431

Cited by 11 publications

(7 citation statements)

References 31 publications

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“…We observed a higher frequency of hypermethylated miRNA genes in ER-compared to ER + tumors from AA women, but a lower frequency of hypermethylation in ER-versus ER + tumors from EA women. Consistent with our ndings for tumors from EA women, several studies focused on DNA methylation of coding genes observed a higher frequency of hypermethylated genes in ER + tumors (8,31,32). One explanation for this may be that ER-related signaling molecules may enhance the activity of DNA methylation transferases to catalyze the transfer of a methyl group to a DNA segment, thus lead to the speci c gain of DNA methylation in ER + tumors.…”

Section: Discussionsupporting

confidence: 90%

Genome-wide DNA methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry

Gong

Chen

Wang

et al. 2020

Preprint

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Background: 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). The reasons remain largely unknown. 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- breast cancer, and their functional role in the regulation of miRNA expression, especially among high risk AA women. Methods: In this study, genome-wide DNA methylation and miRNA expression profiling was performed using the Illumina Infinium HumanMethylation450 Bead Chip platform and miRNA sequencing (miRNA-seq) in breast tumors from both AA and EA women. Results: The genome-wide methylation screen identified a total of 7,191 unique CpGs mapped to 1,292 miRNA genes, which correspond to 2,035 unique mature miRNAs. Cluster analysis of these miRNA-associated methylation loci showed a clear pattern of ER-subtype differences. 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 of DNA methylation and corresponding miRNA expression 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. Further 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, cytoskeleton remodeling, angiogenesis, EMT, and others such as signal transduction TGF-β, Wnt, NOTCH, and ESR1-mediated signaling pathways. Conclusions: 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 shed light on the epigenetic regulation of miRNA expression and provide insights into the relations of clinical-relevant miRNAs to their target genes and to serve as potential preventative and therapeutic targets.

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Section: Discussionsupporting

confidence: 90%

Genome-wide DNA methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry

Gong

Chen

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…We observed a higher frequency of hypermethylated miRNA genes in ER-compared to ER+ tumors from AA women, but a lower frequency of hypermethylation in ER-versus ER+ tumors from EA women. Consistent with our findings for tumors from EA women, several studies focused on DNA methylation of coding genes observed a higher frequency of hypermethylated genes in ER+ tumors [8,30,31]. One explanation for this may be that ER-related signaling molecules may modify the activity of DNA methylation transferases that catalyze the transfer of a methyl group to a DNA segment and/or enzymes involved in demethylation of DNA (e.g., TET1-3, APOBEC), thus lead to the specific gain of DNA methylation in ER+ tumors.…”

Section: Plos Onesupporting

confidence: 92%

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

et al. 2021

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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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“…S4). DNA methylation has been implicated as a mechanism to silence ERα expression in ERα − BrC (24). Three CpG islands are predicted in the ERα promoter regions (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

Cell lineage tracing links ERα loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype

Ding

Liu

Lee

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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HER2-positive (HER2+) breast cancers (BrCs) contain approximately equal numbers of ERα+HER2+ and ERα−HER2+ cases. An enduring obstacle is the unclear cell lineage-related characteristics of these BrCs. Although ERα+HER2+ BrCs could lose ERα to become ERα−HER2+ BrCs, direct evidence is missing. To investigate ERα dependencies and their implications during BrC growth and metastasis, we generated ERαCreRFP-T mice that produce an RFP-marked ERα+ mammary gland epithelial cell (MGEC) lineage. RCAS virus-mediated expression of Erbb2, a rodent Her2 homolog, first produced comparable numbers of ERα+RFP+Erbb2+ and ERα−RFP−Erbb2+ MGECs. Early hyperplasia developed mostly from ERα+RFP+Erbb2+ cells and ERα−RFP−Erbb2+ cells in these lesions were rare. The subsequently developed ductal carcinomas in situ had 64% slow-proliferating ERα+RFP+Erbb2+ cells, 15% fast-proliferating ERα−RFP+Erbb2+ cells derived from ERα+RFP+Erbb2+ cells, and 20% fast-proliferating ERα−RFP−Erbb2+ cells. The advanced tumors had mostly ERα−RFP+Erbb2+ and ERα−RFP−Erbb2+ cells and only a very small population of ERα+RFP+Erbb2+ cells. In ERα−RFP+Erbb2+ cells, GATA3 and FoxA1 decreased expression and ERα promoter regions became methylated, consistent with the loss of ERα expression. Lung metastases consisted of mostly ERα−RFP+Erbb2+ cells, a few ERα−RFP−Erbb2+ cells, and no ERα+RFP+Erbb2+ cells. The high metastatic capacity of ERα−RFP+Erbb2+ cells was associated with ERK1/2 activation. These results show that the slow-proliferating, nonmetastatic ERα+RFP+Erbb2+ cells progressively lose ERα during tumorigenesis to become fast-proliferating, highly metastatic ERα−RFP+Erbb2+ cells. The ERα−Erbb2+ BrCs with an ERα+ origin are more aggressive than those ERα−Erbb2+ BrCs with an ERα− origin, and thus, they should be distinguished and treated differently in the future.

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DNA methylation in breast cancers: Differences based on estrogen receptor status and recurrence

Cited by 11 publications

References 31 publications

Genome-wide DNA methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry

Genome-wide DNA methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry

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

Cell lineage tracing links ERα loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype

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