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MDM4 is a rational target for treating breast cancers with mutant p53
Author(s) -
Miranda Panimaya Jeffreena,
Buckley Daniel,
Raghu Dinesh,
Pang JiaMin B,
Takano Elena A,
Vijayakumaran Reshma,
Teunisse Amina FAS,
Posner Atara,
Procter Tahlia,
Herold Marco J,
Gamell Cristina,
Marine JeanChristophe,
Fox Stephen B,
Jochemsen Aart,
Haupt Sue,
Haupt Ygal
Publication year - 2017
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4877
Subject(s) - mutant , triple negative breast cancer , gene knockdown , cancer research , biology , context (archaeology) , targeted therapy , breast cancer , cancer , apoptosis , genetics , gene , paleontology
Abstract 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.