A Cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation

Z.R. Yu, C.G. Wang, M. Wang, Z.P. Li, M.C. Casimiro, M.R. Liu, K.M. Wu, James Whittle, X.M. Ju, T. Hyslop, P. Mccue, R.G. Pestell

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    Abstract

    Decreased expression of specific microRNAs (miRNAs) occurs in human tumors, which suggests a function for miRNAs in tumor suppression. Herein, levels of the miR-17-5p/miR-20a miRNA cluster were inversely correlated to cyclin D1 abundance in human breast tumors and cell lines. MiR-17/20 suppressed breast cancer cell proliferation and tumor colony formation by negatively regulating cyclin D1 translation via a conserved 3′ untranslated region miRNA-binding site, thereby inhibiting serum-induced S phase entry. The cell cycle effect of miR-17/20 was abrogated by cyclin D1 siRNA and in cyclin D1–deficient breast cancer cells. Mammary epithelial cell–targeted cyclin D1 expression induced miR-17-5p and miR-20a expression in vivo, and cyclin D1 bound the miR-17/20 cluster promoter regulatory region. In summary, these studies identify a novel cyclin D1/miR-17/20 regulatory feedback loop through which cyclin D1 induces miR-17-5p/miR-20a. In turn, miR-17/20 limits the proliferative function of cyclin D1, thus linking expression of a specific miRNA cluster to the regulation of oncogenesis.
    Original languageEnglish
    Pages (from-to)509-517
    JournalJournal of Cell Biology
    Volume182
    Issue number3
    DOIs
    Publication statusPublished - 2008

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