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Oncogene. 2015 Jul 23;34(30):3895-907. doi: 10.1038/onc.2014.430. Epub 2014 Dec 22.

MiR-873 regulates ERα transcriptional activity and tamoxifen resistance via targeting CDK3 in breast cancer cells.

Author information

1
Institute of Disease Control and Prevention, Chinese Academy of Military Medical Sciences, Beijing, China.
2
Beijing Institute for Neuroscience, Capital Medical University, Beijing, China.
3
Department of Molecular & Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, KY, USA.
4
The Affiliated Hospital of Jiujiang University, Jiujiang, China.
5
Department of Animal Sciences and Technology, Jilin Agriculture University, Changchun, China.
6
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
7
Urology Department, the First Hospital of Nanchang University, Nanchang, China.
8
Department of Applied Chemistry, College of Chemistry & Molecular Engineering, Peking University, Beijing, China.
9
Department of Chemistry, College of Arts and Sciences, Indiana University-Purdue University Fort Wayne Fort Wayne, IN, USA.
10
Institute of Health Sciences, Anhui University, Hefei, China.

Abstract

miRNAs (microRNAs) are frequently and aberrantly expressed in many cancers. MiR-873 has been revealed to be downregulated in colorectal cancer and glioblastoma. However, its function remains unclear. Here we report that miR-873 is downregulated in breast tumor compared with normal tissue. Enforced expression of miR-873 decreases the transcriptional activity of ER (estrogen receptor)-α but not ERβ through the modulation of ERα phosphorylation in ER-positive breast cancer cells. We also found that miR-873 inhibits breast cancer cell proliferation and tumor growth in nude mice. Reporter gene assays revealed cyclin-dependent kinase 3 (CDK3) as a direct target of miR-873. CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3. Interestingly, miR-873 was observed to be downregulated in tamoxifen-resistant MCF-7/TamR cells, while CDK3 is overexpressed in these cells. More importantly, re-expression of miR-873 reversed tamoxifen resistance in MCF-7/TamR cells. Our data demonstrate that miR-873 is a novel tumor suppressor in ER-positive breast cancer and a potential therapeutic approach for treatment of tamoxifen-resistant breast cancer.

PMID:
25531331
DOI:
10.1038/onc.2014.430
[Indexed for MEDLINE]

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