title: Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem-cell-like state.
abstract: The miR-200 family is a key regulator of the epithelial-mesenchymal transition, however, its role in controlling the transition between cancer stem-cell-like and non-stem-cell-like phenotypes is not well understood. We utilized immortalized human mammary epithelial (HMLE) cells to investigate the regulation of the miR-200 family during their conversion to a stem-like phenotype. HMLE cells were found to be capable of spontaneous conversion from a non-stem to a stem-like phenotype and this conversion was accompanied by the loss of miR-200 expression. Stem-like cell fractions isolated from metastatic breast cancers also displayed loss of miR-200 indicating similar molecular changes may occur during breast cancer progression. The phenotypic change observed in HMLE cells was directly controlled by miR-200 because restoration of its expression decreased stem-like properties while promoting a transition to an epithelial phenotype. Investigation of the mechanisms controlling miR-200 expression revealed both DNA methylation and histone modifications were significantly altered in the stem-like and non-stem phenotypes. In particular, in the stem-like phenotype, the miR-200b-200a-429 cluster was silenced primarily through polycomb group-mediated histone modifications whereas the miR-200c-141 cluster was repressed by DNA methylation. These results indicate that the miR-200 family plays a crucial role in the transition between stem-like and non-stem phenotypes and that distinct epigenetic-based mechanisms regulate each miR-200 gene in this process. Therapy targeted against miR-200 family members and epigenetic modifications might therefore be applicable to breast cancer.
authors.affiliation: Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, SA 5000, Australia.
authors.forename: Yat-Yuen
authors.initials: YY
authors.lastname: Lim
authors.forename: Josephine A
authors.initials: JA
authors.lastname: Wright
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Attema
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gregory
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Bert
authors.forename: Eric
authors.initials: E
authors.lastname: Smith
authors.forename: Daniel
authors.initials: D
authors.lastname: Thomas
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.forename: Paul A
authors.initials: PA
authors.lastname: Drew
authors.forename: Yeesim
authors.initials: Y
authors.lastname: Khew-Goodall
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Goodall
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D002461:Cell Line, Transformed; D019175:DNA Methylation; D063185:Epigenetic Repression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D019076:Transgenes / Q000235:genetics
chemical_list: D006657:Histones; C533896:MIRN200 microRNA, human; D035683:MicroRNAs
keywords: Breast cancer stem cells; DNA methylation; Epithelial–mesenchymal transition; Gene regulation; Histone modifications; miR-200