MCF-7 as a Model for Functional Analysis of Breast Cancer Risk Variants
Breast cancer genetic predisposition is governed by more than 142 loci as revealed by genome-wide association studies (GWAS). The functional contribution of these risk loci to breast cancer remains unclear, and additional post-GWAS analyses are required. We identified active regulatory elements (enh...
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| Published in: | Cancer epidemiology, biomarkers & prevention Vol. 28; no. 10; pp. 1735 - 1745 |
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| Main Authors: | , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
01-10-2019
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| Online Access: | Get full text |
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| Summary: | Breast cancer genetic predisposition is governed by more than 142 loci as revealed by genome-wide association studies (GWAS). The functional contribution of these risk loci to breast cancer remains unclear, and additional post-GWAS analyses are required.
We identified active regulatory elements (enhancers, promoters, and chromatin organizing elements) by histone H3K27 acetylation and CTCF occupancy and determined the enrichment of risk variants at these sites. We compared these results with previously published data and for other cell lines, including human mammary epithelial cells, and related these data to gene expression.
In terms of mapping accuracy and resolution, our data augment previous annotations of the MCF-7 epigenome. After intersection with GWAS risk variants, we found 39 enhancers and 15 CTCF occupancy sites that, between them, overlapped 96 breast cancer credible risk variants at 42 loci. These risk enhancers likely regulate the expression of dozens of genes, which are enriched for GO categories, including estrogen and prolactin signaling.
Ten (of 142) breast cancer risk loci likely function via enhancers that are active in MCF-7 and are well suited to targeted manipulation in this system. In contrast, risk loci cannot be mapped to specific CTCF-binding sites, and the genes linked to risk CTCF sites did not show functional enrichment. The identity of risk enhancers and their associated genes suggests that some risk may function during later processes in cancer progression.
Here, we report how the ER
cell line MCF-7 can be used to dissect risk mechanisms for breast cancer. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authors’ contributions These authors co-directed this work. AB performed all in vitro and molecular biology work, performed the analysis of CTCF ChIP-Seq data. GC directed experimental planning and design, advised on results, and edited the manuscript. SP directed experimental planning and design, supervised and/or performed primary RNA-seq and ChIP-Seq data analysis, collated BCa GWAS SNPs, performed the analysis for risk variant enrichment in H3K27ac sites. All authors read and approved the final manuscript. |
| ISSN: | 1055-9965 1538-7755 |
| DOI: | 10.1158/1055-9965.EPI-19-0066 |