title: Estrogen mediated-activation of miR-191/425 cluster modulates tumorigenicity of breast cancer cells depending on estrogen receptor status.
abstract: MicroRNAs (miRNAs), single-stranded non-coding RNAs, influence myriad biological processes that can contribute to cancer. Although tumor-suppressive and oncogenic functions have been characterized for some miRNAs, the majority of microRNAs have not been investigated for their ability to promote and modulate tumorigenesis. Here, we established that the miR-191/425 cluster is transcriptionally dependent on the host gene, DALRD3, and that the hormone 17β-estradiol (estrogen or E2) controls expression of both miR-191/425 and DALRD3. MiR-191/425 locus characterization revealed that the recruitment of estrogen receptor α (ERα) to the regulatory region of the miR-191/425-DALRD3 unit resulted in the accumulation of miR-191 and miR-425 and subsequent decrease in DALRD3 expression levels. We demonstrated that miR-191 protects ERα positive breast cancer cells from hormone starvation-induced apoptosis through the suppression of tumor-suppressor EGR1. Furthermore, enforced expression of the miR-191/425 cluster in aggressive breast cancer cells altered global gene expression profiles and enabled us to identify important tumor promoting genes, including SATB1, CCND2, and FSCN1, as targets of miR-191 and miR-425. Finally, in vitro and in vivo experiments demonstrated that miR-191 and miR-425 reduced proliferation, impaired tumorigenesis and metastasis, and increased expression of epithelial markers in aggressive breast cancer cells. Our data provide compelling evidence for the transcriptional regulation of the miR-191/425 cluster and for its context-specific biological determinants in breast cancers. Importantly, we demonstrated that the miR-191/425 cluster, by reducing the expression of an extensive network of genes, has a fundamental impact on cancer initiation and progression of breast cancer cells.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, School of Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Gianpiero
authors.initials: G
authors.lastname: Di Leva
authors.forename: Claudia
authors.initials: C
authors.lastname: Piovan
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gasparini
authors.forename: Apollinaire
authors.initials: A
authors.lastname: Ngankeu
authors.forename: Cristian
authors.initials: C
authors.lastname: Taccioli
authors.forename: Daniel
authors.initials: D
authors.lastname: Briskin
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Cheung
authors.forename: Brad
authors.initials: B
authors.lastname: Bolon
authors.forename: Laura
authors.initials: L
authors.lastname: Anderlucci
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Gerard
authors.initials: G
authors.lastname: Nuovo
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.forename: Marilena V
authors.initials: MV
authors.lastname: Iorio
authors.forename: Marco
authors.initials: M
authors.lastname: Galasso
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Santhanam
authors.forename: Santhanam
authors.initials: S
authors.lastname: Ramasamy
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: Kimerly A
authors.initials: KA
authors.lastname: Powell
authors.forename: Anna
authors.initials: A
authors.lastname: Bratasz
authors.forename: Michela
authors.initials: M
authors.lastname: Garofalo
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism
chemical_list: C497325:EGR1 protein, human; C506487:ESR1 protein, human; D051766:Early Growth Response Protein 1; D047628:Estrogen Receptor alpha; D004967:Estrogens; C546177:MIRN191 microRNA, human; C555677:MIRN425 microRNA, human; D035683:MicroRNAs