MicroRNAs Link Estrogen Receptor Alpha Status and Dicer Levels in Breast Cancer

被引：119
作者：
Cochrane D.R. [1 ]
Cittelly D.M. [1 ]
Howe E.N. [1 ]
Spoelstra N.S. [1 ]
McKinsey E.L. [1 ]
LaPara K. [3 ]
Elias A. [2 ]
Yee D. [3 ]
Richer J.K. [1 ]
机构：
[1] Department of Pathology, University of Colorado Denver, Aurora, CO 80045, Mail Stop 8104
[2] Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora
[3] Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
来源：
Hormones and Cancer | 2010年 / 1卷 / 6期
基金：
美国国家卫生研究院;
关键词：
Breast cancer; Dicer; Epithelial to mesenchymal transition; ESR1; miRNA;
D O I：
10.1007/s12672-010-0043-5
中图分类号：
学科分类号：
摘要：
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. © 2010 Springer Science+Business Media, LLC.
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页码：306 / 319
页数：13
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