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Published online
doi:10.1083/jcb.200801079
The Journal of Cell Biology, Vol. 182, No. 3, 509-517
The Rockefeller University Press, 0021-9525 $30.00
© Yu et al.
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Article

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



Zuoren Yu1, Chenguang Wang1,2, Min Wang1, Zhiping Li1, Mathew C. Casimiro1, Manran Liu1, Kongming Wu1, James Whittle3, Xiaoming Ju1, Terry Hyslop4, Peter McCue5, and Richard G. Pestell1,2

1 Department of Cancer Biology and 2 Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
3 The University of Western Australia, Crawley 6009, Western Australia, Australia
4 Division of Biostatistics and 5 Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University Hospital, Philadelphia, PA 19107

Correspondence to Richard G. Pestell: richard.pestell{at}jefferson.edu

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.

Abbreviations used in this paper: MEF, mouse embryonic fibroblast; miRNA, microRNA; MMTV, mouse mammary tumor virus; MSCV, mouse stem cell virus; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; UTR, untranslated region.

© 2008 Yu et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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