title: miRNA-34b as a tumor suppressor in estrogen-dependent growth of breast cancer cells.
abstract: BACKGROUND
  Estrogen is involved in several physiological and pathological processes through estrogen receptor (ER)-mediated transcriptional gene regulation. miRNAs (miRs), which are noncoding RNA genes, may respond to estrogen and serve as posttranscriptional regulators in tumorigenic progression, especially in breast cancer; however, only limited information about this possibility is available. In the present study, we identified the estrogen-regulated miR-34b and investigated its functional role in breast cancer progression.
  
  
  METHODS
  Estrogen-regulated miRNAs were identified by using a TaqMan low density array. Our in vivo Tet-On system orthotopic model revealed the tumor-suppressive ability of miR-34b. Luciferase reporter assays and chromatin immunoprecipitation assay demonstrated miR-34b were regulated by p53-ER interaction.
  
  
  RESULTS
  In this study, we identified one such estrogen downregulated miRNA, miR-34b, as an oncosuppressor that targets cyclin D1 and Jagged-1 (JAG1) in an ER+/wild-type p53 breast cancer cell line (MCF-7), as well as in ovarian and endometrial cells, but not in ER-negative or mutant p53 breast cancer cell lines (T47D, MBA-MB-361 and MDA-MB-435). There is a negative association between ERα and miR-34b expression levels in ER+ breast cancer patients. Tet-On induction of miR-34b can cause inhibition of tumor growth and cell proliferation. Also, the overexpression of miR-34b inhibited ER+ breast tumor growth in an orthotopic mammary fat pad xenograft mouse model. Further validation indicated that estrogen's inhibition of miR-34b expression was mediated by interactions between ERα and p53, not by DNA methylation regulation. The xenoestrogens diethylstilbestrol and zeranol also showed similar estrogenic effects by inhibiting miR-34b expression and by restoring the protein levels of the miR-34b targets cyclin D1 and JAG1 in MCF-7 cells.
  
  
  CONCLUSIONS
  These findings reveal that miR-34b is an oncosuppressor miRNA requiring both ER+ and wild-type p53 phenotypes in breast cancer cells. These results improve our ability to develop new therapeutic strategies to target the complex estrogenic pathway in human breast cancer progression through miRNA regulation.
authors: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, No, 1, Sec, 1, Ren-Ai Road, Taipei, 100, Taiwan.
authors: Yee-Ming
authors: YM
authors: Lee
authors: Jen-Yi
authors: JY
authors: Lee
authors: Chao-Chi
authors: CC
authors: Ho
authors: Qi-Sheng
authors: QS
authors: Hong
authors: Sung-Liang
authors: SL
authors: Yu
authors: Chii-Ruey
authors: CR
authors: Tzeng
authors: Pan-Chyr
authors: PC
authors: Yang
authors: Huei-Wen
authors: HW
authors: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D008954:Models, Biological; D009367:Neoplasm Staging; D011960:Receptors, Estrogen / Q000235:genetics; D000072099:Serrate-Jagged Proteins; D013629:Tamoxifen / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D002135:Calcium-Binding Proteins; D004967:Estrogens; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; C522425:MIRN34 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D011960:Receptors, Estrogen; D000072099:Serrate-Jagged Proteins; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; D019938:Cyclin D1