title: Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas.
abstract: Tamoxifen, a small-molecule antagonist of the transcription factor estrogen receptor alpha (ERα) used to treat breast cancer, increases risks of endometrial cancer. However, no parallels of ERα transcriptional action in breast and endometrial tumors have been found that might explain this effect. In this study, we addressed this issue with a genome-wide assessment of ERα-chromatin interactions in surgical specimens obtained from patients with tamoxifen-associated endometrial cancer. ERα was found at active enhancers in endometrial cancer cells as marked by the presence of RNA polymerase II and the histone marker H3K27Ac. These ERα binding sites were highly conserved between breast and endometrial cancer and enriched in binding motifs for the transcription factor FOXA1, which displayed substantial overlap with ERα binding sites proximal to genes involved in classical ERα target genes. Multifactorial ChIP-seq data integration from the endometrial cancer cell line Ishikawa illustrated a functional genomic network involving ERα and FOXA1 together with the enhancer-enriched transcriptional regulators p300, FOXM1, TEAD4, FNFIC, CEBP8, and TCF12. Immunohistochemical analysis of 230 primary endometrial tumor specimens showed that lack of FOXA1 and ERα expression was associated with a longer interval between breast cancer and the emergence of endometrial cancer, exclusively in tamoxifen-treated patients. Our results define conserved sites for a genomic interplay between FOXA1 and ERα in breast cancer and tamoxifen-associated endometrial cancer. In addition, FOXA1 and ERα are associated with the interval time between breast cancer and endometrial cancer only in tamoxifen-treated breast cancer patients. Cancer Res; 76(13); 3773-84. ©2016 AACR.
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Droog
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Nevedomskaya
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Yongsoo
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Tesa
authors.initials: T
authors.lastname: Severson
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Koen D
authors.initials: KD
authors.lastname: Flach
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Opdam
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Karianne
authors.initials: K
authors.lastname: Schuurman
authors.affiliation: Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Gradowska
authors.affiliation: Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Hauptmann
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Gwen
authors.initials: G
authors.lastname: Dackus
authors.affiliation: Department of Pathology, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Hollema
authors.affiliation: Department of Gynecological Oncology, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: Mourits
authors.affiliation: Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: Nederlof
authors.affiliation: Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Hester
authors.initials: H
authors.lastname: van Boven
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
authors.affiliation: Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands. Faculty of EEMCS, Delft University of Technology, Delft, the Netherlands.
authors.forename: Lodewyk
authors.initials: L
authors.lastname: Wessels
authors.affiliation: Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Flora E
authors.initials: FE
authors.lastname: van Leeuwen
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. w.zwart@nki.nl.
authors.forename: Wilbert
authors.initials: W
authors.lastname: Zwart
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020218:Response Elements / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013629:Tamoxifen / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D012333:RNA, Messenger; D013629:Tamoxifen