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

• DOI: 10.1002/path.4877
• Publication Date: 2017-01-18T05:51:56Z
• Authors: Panimaya Jeffreen...; Daniel Buckley; Dinesh Raghu; Jia‐Min B Pang; Elena A Takano; Reshma Vijayakumaran; Amina FAS Teunisse; Atara Posner; Tahlia Procter; Marco J Herold; Cristina Gamell; Jean‐Christophe M...; Stephen B Fox; Aart Jochemsen; Sue Haupt; Ygal Haupt
• Keywords: P53 protein

Mutation of the key tumour suppressor p53 defines a transition in progression towards aggressive and metastatic breast cancer (BC) with poorest outcome. Specifically, mutation frequency exceeds 50% triple-negative BC. Key regulators mutant that facilitate its oncogenic functions are potential therapeutic targets. We report here MDM4 protein is frequently abundant context basal-like BC samples. Importantly, we show plays critical role proliferation these cells. demonstrate conditional knockdown (KD) provokes growth inhibition across range subtypes p53, including luminal, Her2+ BCs. In vivo, was shown to be crucial for establishment tumours. This mediated, at least part, by cell cycle inhibitor p27. Depletion p27 together KD led recovery proliferative capacity cells were growth-inhibited alone. Consistently, identified low levels expression tumours corresponding high p53. predicts signature subset may amenable therapies targeted The as target vitro use small-molecule inhibitor. Overall, our study supports novel expressing Copyright © 2017 Pathological Society Great Britain Ireland. Published John Wiley & Sons, Ltd.