MDM4 is a rational target for treating breast cancers with mutant p53.

Autor:	Miranda PJ; Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia., Buckley D; Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia., Raghu D; Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia., Pang JB; Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Takano EA; Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Vijayakumaran R; Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia., Teunisse AF; Department of Molecular Cell Biology, University Medical Centre, Leiden, The Netherlands., Posner A; Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia., Procter T; Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia., Herold MJ; Molecular Genetics of Cancer, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia., Gamell C; Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia., Marine JC; Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory for Molecular Cancer Biology, Department of Oncology, KULeuven, Leuven, Belgium., Fox SB; Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Jochemsen A; Department of Molecular Cell Biology, University Medical Centre, Leiden, The Netherlands., Haupt S; Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia., Haupt Y; Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.; Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.
Jazyk:	angličtina
Zdroj:	The Journal of pathology [J Pathol] 2017 Apr; Vol. 241 (5), pp. 661-670. Date of Electronic Publication: 2017 Mar 01.
DOI:	10.1002/path.4877
Abstrakt:	Mutation of the key tumour suppressor p53 defines a transition in the progression towards aggressive and metastatic breast cancer (BC) with the poorest outcome. Specifically, the p53 mutation frequency exceeds 50% in triple-negative BC. Key regulators of mutant p53 that facilitate its oncogenic functions are potential therapeutic targets. We report here that the MDM4 protein is frequently abundant in the context of mutant p53 in basal-like BC samples. Importantly, we show that MDM4 plays a critical role in the proliferation of these BC cells. We demonstrate that conditional knockdown (KD) of MDM4 provokes growth inhibition across a range of BC subtypes with mutant p53, including luminal, Her2 + and triple-negative BCs. In vivo, MDM4 was shown to be crucial for the establishment and progression of tumours. This growth inhibition was mediated, at least in part, by the cell cycle inhibitor p27. Depletion of p27 together with MDM4 KD led to recovery of the proliferative capacity of cells that were growth-inhibited by MDM4 KD alone. Consistently, we identified low levels of p27 expression in basal-like tumours corresponding to high levels of MDM4 and p53. This predicts a signature for a subset of tumours that may be amenable to therapies targeted towards MDM4 and mutant p53. The therapeutic potential of MDM4 as a target in BC with mutant p53 was shown in vitro by use of a small-molecule inhibitor. Overall, our study supports MDM4 as a novel therapeutic target for BC expressing mutant p53. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
Databáze:	MEDLINE
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