RT Journal
A1 Joosten, Stacey E.P.
A1 Gregoricchio, Sebastian
A1 Stelloo, Suzan
A1 Yapıcı, Elif
A1 Huang, Chia-Chi Flora
A1 Yavuz, Kerim
A1 Donaldson Collier, Maria
A1 Morova, Tunç
A1 Altintaş, Umut Berkay
A1 Kim, Yongsoo
A1 Canisius, Sander
A1 Moelans, Cathy B.
A1 van Diest, Paul J.
A1 Korkmaz, Gozde
A1 Lack, Nathan A.
A1 Vermeulen, Michiel
A1 Linn, Sabine C.
A1 Zwart, Wilbert
T1 Estrogen receptor 1 chromatin profiling in human breast tumors reveals high inter-patient heterogeneity with enrichment of risk SNPs and enhancer activity at most-conserved regions
JF Genome Research 
JO Genome Research 
YR 2024 
FD April 01 
VO 34 
IS 4 
SP 539 
OP 555 
DO 10.1101/gr.278680.123 
UL http://genome.cshlp.org/content/34/4/539.abstract 
AB Estrogen Receptor 1 (ESR1; also known as ERα, encoded by ESR1 gene) is the main driver and prime drug target in luminal breast cancer. ESR1 chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ESR1 chromatin action, along with its biological implications. Here, we use a large set of ESR1 ChIP-seq data from 70 ESR1+ breast cancers to explore inter-patient heterogeneity in ESR1 DNA binding to reveal a striking inter-tumor heterogeneity of ESR1 action. Of note, commonly shared ESR1 sites show the highest estrogen-driven enhancer activity and are most engaged in long-range chromatin interactions. In addition, the most commonly shared ESR1-occupied enhancers are enriched for breast cancer risk SNP loci. We experimentally confirm SNVs to impact chromatin binding potential for ESR1 and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we can confirm these variations to associate with differences in expression for the target gene. Cumulatively, we reveal a natural hierarchy of ESR1–chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ESR1 landscape, with the most common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.