title: Epigenetic silencing of miR-200c in breast cancer is associated with aggressiveness and is modulated by ZEB1.
abstract: Loss of expression of miR-200 family members has been implicated in cellular plasticity, a phenomenon that accounts for epithelial-to-mesenchymal transition (EMT) and stem-like features of many carcinomas and is considered a major cause of tumor aggressiveness and drug resistance. Nevertheless, the mechanisms of miR-200 downregulation in breast cancer are still largely unknown. Here we show that miR-200c expression inversely correlates with miR-200c/miR-141 locus methylation in triple-negative breast tumors (TNBC). Importantly, low levels of miR-200c expression and high levels of miR-200c/miR-141 locus methylation associated with lymph node metastasis. Moreover, miR-200c/miR-141 locus methylation was significantly related to high expression of ZEB1 in two independent TNBC series. Silencing of ZEB1 in vitro reduced miR-200c/miR-141 DNA methylation and, concurrently, decreased histone H3K9 trimethylation. This chromatin modifications were paralleled by an increase in the expression of both miR-200c and E-cadherin. Similar effects were achieved by treatment with a demethylating agent. Our data suggest that gene methylation is an important element in the regulation of the miR-200c/ZEB1 axis and that chromatin remodeling of the miR-200c/miR-141 locus is affected by ZEB1 and, thus, contributes to ZEB1-induced cellular plasticity. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Damiano
authors.affiliation: Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Brisotto
authors.affiliation: Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Borgna
authors.affiliation: Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: di Gennaro
authors.affiliation: Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Armellin
authors.affiliation: Pathology, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Perin
authors.affiliation: Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy.|Medical Oncology Department, Gastrointestinal Unit, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Guardascione
authors.affiliation: Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Maestro
authors.affiliation: Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy.
authors.forename: Manuela
authors.identifier: 0000-0001-7682-2578
authors.initials: M
authors.lastname: Santarosa
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics*; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D014407:Tumor Cells, Cultured; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1