title: MicroRNAs link estrogen receptor alpha status and Dicer levels in breast cancer.
abstract: To identify microRNAs (miRNAs) associated with estrogen receptor (ESR1) status, we profiled luminal A, ESR1+ breast cancer cell lines versus triple negative (TN), which lack ERα, progesterone receptor and Her2/neu. Although two thirds of the differentially expressed miRNAs are higher in ESR1+ breast cancer cells, some miRNAs, such as miR-222/221 and miR-29a, are dramatically higher in ESR1- cells (∼100- and 16-fold higher, respectively). MiR-222/221 (which target ESR1 itself) and miR-29a are predicted to target the 3' UTR of Dicer1. Addition of these miRNAs to ESR1+ cells reduces Dicer protein, whereas antagonizing miR-222 in ESR1- cells increases Dicer protein. We demonstrate via luciferase reporter assays that these miRNAs directly target the Dicer1 3' UTR. In contrast, miR-200c, which promotes an epithelial phenotype, is 58-fold higher in the more well-differentiated ERα+ cells, and restoration of miR-200c to ERα- cells causes increased Dicer protein, resulting in increased levels of other mature miRNAs typically low in ESR1- cells. Together, our findings explain why Dicer is low in ERα negative breast cancers, since such cells express high miR-221/222 and miR-29a levels (which repress Dicer) and low miR-200c (which positively affect Dicer levels). Furthermore, we find that miR-7, which is more abundant in ERα+ cells and is estrogen regulated, targets growth factor receptors and signaling intermediates such as EGFR, IGF1R, and IRS-2. In summary, miRNAs differentially expressed in ERα+ versus ERα- breast cancers actively control some of the most distinguishing characteristics of the luminal A and TN subtypes, such as ERα itself, Dicer, and growth factor receptor levels.
authors.affiliation: Department of Pathology, University of Colorado Denver, Mail Stop 8104, P.O. Box 6511, Aurora, CO 80045, USA.
authors.forename: Dawn R
authors.initials: DR
authors.lastname: Cochrane
authors.forename: Diana M
authors.initials: DM
authors.lastname: Cittelly
authors.forename: Erin N
authors.initials: EN
authors.lastname: Howe
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Spoelstra
authors.forename: Erin L
authors.initials: EL
authors.lastname: McKinsey
authors.forename: Kelly
authors.initials: K
authors.lastname: LaPara
authors.forename: Anthony
authors.initials: A
authors.lastname: Elias
authors.forename: Douglas
authors.initials: D
authors.lastname: Yee
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Richer
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D043244:Ribonuclease III / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D035683:MicroRNAs; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases