miRNA-34b as a tumor suppressor in estrogen-dependent growth of breast cancer cells
Journal
Breast Cancer Research
Journal Volume
13
Journal Issue
6
Date Issued
2011
Author(s)
Abstract
Introduction: 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. ? 2011 Lee et al.; licensee BioMed Central Ltd.
SDGs
Other Subjects
cyclin D1; diethylstilbestrol; estrogen; estrogen receptor alpha; Jagged1; luciferase; microRNA; microRNA 34b; protein p53; tumor suppressor protein; unclassified drug; zeranol; antineoplastic hormone agonists and antagonists; calcium binding protein; cyclin D1; estrogen; estrogen receptor; membrane protein; microRNA; MIRN34 microRNA, human; protein p53; Serrate proteins; signal peptide; tamoxifen; adult; aged; animal experiment; animal model; article; breast cancer; cancer cell; cancer growth; cancer inhibition; carcinogenesis; cell proliferation; chromatin immunoprecipitation; clinical article; controlled study; DNA methylation; down regulation; endometrium cell; estrogen activity; female; human; human cell; in vivo study; mouse; nonhuman; ovary cell; animal; biological model; breast tumor; cancer staging; drug effect; drug screening; gene expression; gene expression profiling; genetics; metabolism; middle aged; mouse mutant; nude mouse; pathology; tumor cell line; tumor suppressor gene; Adult; Aged; Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Calcium-Binding Proteins; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Estrogens; Female; Gene Expression; Gene Expression Profiling; Genes, Tumor Suppressor; Humans; Intercellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Mice, Nude; Mice, SCID; MicroRNAs; Middle Aged; Models, Biological; Neoplasm Staging; Receptors, Estrogen; Tamoxifen; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays
Type
journal article