title: MiR-873 regulates ERα transcriptional activity and tamoxifen resistance via targeting CDK3 in breast cancer cells.
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.
authors.affiliation: Institute of Disease Control and Prevention, Chinese Academy of Military Medical Sciences, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Cui
authors.affiliation: Beijing Institute for Neuroscience, Capital Medical University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular & Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: The Affiliated Hospital of Jiujiang University, Jiujiang, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Leng
authors.affiliation: The Affiliated Hospital of Jiujiang University, Jiujiang, China.
authors.forename: K
authors.initials: K
authors.lastname: Qian
authors.affiliation: Department of Animal Sciences and Technology, Jilin Agriculture University, Changchun, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute of Disease Control and Prevention, Chinese Academy of Military Medical Sciences, Beijing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Urology Department, the First Hospital of Nanchang University, Nanchang, China.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Urology Department, the First Hospital of Nanchang University, Nanchang, China.
authors.forename: T
authors.initials: T
authors.lastname: Sun
authors.affiliation: Institute of Disease Control and Prevention, Chinese Academy of Military Medical Sciences, Beijing, China.
authors.forename: R
authors.initials: R
authors.lastname: Wu
authors.affiliation: Institute of Disease Control and Prevention, Chinese Academy of Military Medical Sciences, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Institute of Disease Control and Prevention, Chinese Academy of Military Medical Sciences, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Applied Chemistry, College of Chemistry & Molecular Engineering, Peking University, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Chemistry, College of Arts and Sciences, Indiana University-Purdue University Fort Wayne Fort Wayne, IN, USA.
authors.forename: P
authors.initials: P
authors.lastname: Jing
authors.affiliation: Institute of Health Sciences, Anhui University, Hefei, China.
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.affiliation: Institute of Disease Control and Prevention, Chinese Academy of Military Medical Sciences, Beijing, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D049109:Cell Proliferation; D056849:Cyclin-Dependent Kinase 3 / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000502:physiology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D013629:Tamoxifen / Q000494:pharmacology*; D015533:Transcriptional Activation; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C000598459:MIRN873 microRNA, human; D035683:MicroRNAs; D013629:Tamoxifen; C098776:CDK3 protein, human; D056849:Cyclin-Dependent Kinase 3