title: Suppression of indoleamine-2,3-dioxygenase 1 expression by promoter hypermethylation in ER-positive breast cancer.
abstract: Kynurenine formation by tryptophan-catabolic indoleamine-2,3-dioxygenase 1 (IDO1) plays a key role in tumor immune evasion and inhibition of IDO1 is efficacious in preclinical models of breast cancer. As the response of breast cancer to immune checkpoint inhibitors may be limited, a better understanding of the expression of additional targetable immunomodulatory pathways is of importance. We therefore investigated the regulation of IDO1 expression in different breast cancer subtypes. We identified estrogen receptor α (ER) as a negative regulator of IDO1 expression. Serum kynurenine levels as well as tumoral IDO1 expression were lower in patients with ER-positive than ER-negative tumors and an inverse relationship betweenIDO1and estrogen receptor mRNA was observed across 14 breast cancer data sets. Analysis of whole genome bisulfite sequencing, 450k, MassARRAY and pyrosequencing data revealed that theIDO1promoter is hypermethylated in ER-positive compared with ER-negative breast cancer. Reduced induction of IDO1 was also observed in human ER-positive breast cancer cell lines. IDO1 induction was enhanced upon DNA demethylation in ER-positive but not in ER-negative cells and methylation of anIDO1promoter construct reducedIDO1expression, suggesting that enhanced methylation of theIDO1promoter suppresses IDO1 in ER-positive breast cancer. The association of ER overexpression with epigenetic downregulation of IDO1 appears to be a particular feature of breast cancer asIDO1was not suppressed byIDO1promoter hypermethylation in the presence of high ER expression in cervical or endometrial cancer.
authors.affiliation: Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Dyah L
authors.initials: DL
authors.lastname: Dewi
authors.affiliation: Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Soumya R
authors.initials: SR
authors.lastname: Mohapatra
authors.affiliation: Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Saioa
authors.initials: S
authors.lastname: Blanco Cabañes
authors.affiliation: Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Isabell
authors.initials: I
authors.lastname: Adam
authors.affiliation: Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Somarribas Patterson
authors.affiliation: Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Berdel
authors.affiliation: Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Masroor
authors.initials: M
authors.lastname: Kahloon
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research - UFZ , Leipzig, Germany.
authors.forename: Loreen
authors.initials: L
authors.lastname: Thürmann
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research - UFZ , Leipzig, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Loth
authors.affiliation: Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Heilmann
authors.affiliation: Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.affiliation: Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Mücke
authors.affiliation: Department of Arctic and Marine Biology, UiT Arctic University of Norway , Tromsø, Norway.
authors.forename: Ines
authors.initials: I
authors.lastname: Heiland
authors.affiliation: Department of Gynecology and Obstetrics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), partner site Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Pauline
authors.initials: P
authors.lastname: Wimberger
authors.affiliation: Department of Gynecology and Obstetrics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), partner site Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jan Dominik
authors.initials: JD
authors.lastname: Kuhlmann
authors.affiliation: Neuroimmun GmbH , Karlsruhe, Germany.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Kellner
authors.affiliation: Department of Obstetrics and Gynecology, University of Heidelberg , Heidelberg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Schott
authors.affiliation: Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases, University Hospital of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.affiliation: Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Gerhäuser
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research - UFZ , Leipzig, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Trump
authors.affiliation: Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; Neurology Clinic and National Center for Tumor Diseases, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Christiane A
authors.initials: CA
authors.lastname: Opitz
keywords: DNA methylation; epigenetics; estrogen receptor; immunosuppression; indoleamine-2,3-dioxygenase; tryptophan metabolism