학술논문
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.
Document Type
Academic Journal
Author
Joosten SEP; Division of Oncogenomics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.; Oncode Institute, The Netherlands.; Gregoricchio S; Division of Oncogenomics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.; Oncode Institute, The Netherlands.; Stelloo S; Oncode Institute, The Netherlands.; Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6500HB Nijmegen, The Netherlands.; Yapıcı E; Koç University School of Medicine, 34450 Istanbul, Turkey.; Koç University Research Center for Translational Medicine (KUTTAM), 34450 Istanbul, Turkey.; Huang CF; Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, V6H 3Z6 Canada.; Yavuz K; Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, V6H 3Z6 Canada.; Donaldson Collier M; Division of Oncogenomics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.; Oncode Institute, The Netherlands.; Morova T; Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, V6H 3Z6 Canada.; Altintaş UB; Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, V6H 3Z6 Canada.; Kim Y; Department of Pathology, Amsterdam University Medical Center, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands.; Canisius S; Division of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.; Moelans CB; Department of Pathology, Utrecht University Medical Centre, 3584 CX Utrecht, The Netherlands.; van Diest PJ; Department of Pathology, Utrecht University Medical Centre, 3584 CX Utrecht, The Netherlands.; Korkmaz G; Koç University School of Medicine, 34450 Istanbul, Turkey.; Koç University Research Center for Translational Medicine (KUTTAM), 34450 Istanbul, Turkey.; Lack NA; Koç University School of Medicine, 34450 Istanbul, Turkey.; Koç University Research Center for Translational Medicine (KUTTAM), 34450 Istanbul, Turkey.; Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, V6H 3Z6 Canada.; Vermeulen M; Oncode Institute, The Netherlands.; Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6500HB Nijmegen, The Netherlands.; Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.; Linn SC; Division of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.; Department of Pathology, Utrecht University Medical Centre, 3584 CX Utrecht, The Netherlands.; Department of Medical Oncology, Antoni van Leeuwenhoek Hospital, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.; Zwart W; Division of Oncogenomics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; w.zwart@nki.nl.; Oncode Institute, The Netherlands.; Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands.
Source
Publisher: Cold Spring Harbor Laboratory Press Country of Publication: United States NLM ID: 9518021 Publication Model: Electronic Cited Medium: Internet ISSN: 1549-5469 (Electronic) Linking ISSN: 10889051 NLM ISO Abbreviation: Genome Res Subsets: MEDLINE
Subject
Language
English
Abstract
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.
(© 2024 Joosten et al.; Published by Cold Spring Harbor Laboratory Press.)
(© 2024 Joosten et al.; Published by Cold Spring Harbor Laboratory Press.)