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Cell Rep. 2014 Oct 9;9(1):248-260. doi: 10.1016/j.celrep.2014.08.069. Epub 2014 Oct 2.

Transformation resistance in a premature aging disorder identifies a tumor-protective function of BRD4.

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National Cancer Institute, NIH, Bethesda, MD 20892, USA.
National Cancer Institute, NIH, Bethesda, MD 20892, USA; Cancer Epigenetics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London WC2A 3PX, UK; UCL Cancer Institute, University College London, London WC1E 6DD, UK.
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Department of Medicine, University of Medicine and Dentistry of New Jersey, Robert-Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address:


Advanced age and DNA damage accumulation are prominent risk factors for cancer. The premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS) provides a unique opportunity for studying the interplay between DNA damage and aging-associated tumor mechanisms, given that HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neoplastic transformation. Resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells, leading to inhibition of oncogenic dedifferentiation. BRD4 also inhibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals. BRD4-mediated tumor protection is clinically relevant given that a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific roles for BRD4 in tumorigenesis.

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