MicroRNA-335 inhibits tumor reinitiation and is silenced through genetic and epigenetic mechanisms in human breast cancer
- Kim J. Png1,
- Mitsukuni Yoshida1,
- Xiang H.-F. Zhang2,
- Weiping Shu2,
- Hyeseung Lee1,
- Andreas Rimner3,
- Timothy A. Chan3,
- Elizabeth Comen4,
- Viktor P. Andrade5,
- Seok Won Kim5,
- Tari A. King5,
- Clifford A. Hudis4,
- Larry Norton4,
- James Hicks6,
- Joan Massagué2,7,8 and
- Sohail F. Tavazoie1,8,9
- 1Laboratory of Systems Cancer Biology, Rockefeller University, New York, New York 10065, USA;
- 2Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA;
- 3Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA;
- 4Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA;
- 5Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA;
- 6Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
- 7Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
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↵8 These authors contributed equally to this work.
Abstract
Post-transcriptional regulators have emerged as robust effectors of metastasis and display deregulated expression through unknown mechanisms. Here, we reveal that the human microRNA-335 locus undergoes genetic deletion and epigenetic promoter hypermethylation in every metastatic derivative obtained from independent patients’ malignant cell populations. Genetic deletion of miR-335 is a common event in human breast cancer, is enriched for in breast cancer metastases, and also correlates with ovarian cancer recurrence. We furthermore identify miR-335 as a robust inhibitor of tumor reinitiation. We thus implicate the miR-335 locus on 7q32.2 as the first selective metastasis suppressor and tumor initiation suppressor locus in human breast cancer.
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Footnotes
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↵9 Corresponding author.
E-MAIL stavazoie{at}mail.rockefeller.edu; FAX (212) 327-7209.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1974211.
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Supplemental material is available for this article.
- Received July 24, 2010.
- Accepted December 13, 2010.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press
