title: MDM4 is a rational target for treating breast cancers with mutant p53.
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.
authors.affiliation: Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.
authors.forename: Panimaya Jeffreena
authors.identifier: 0000-0002-1404-0754
authors.initials: PJ
authors.lastname: Miranda
authors.affiliation: Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Buckley
authors.affiliation: Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Raghu
authors.affiliation: Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Jia-Min B
authors.initials: JB
authors.lastname: Pang
authors.affiliation: Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Takano
authors.affiliation: Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.
authors.forename: Reshma
authors.initials: R
authors.lastname: Vijayakumaran
authors.affiliation: Department of Molecular Cell Biology, University Medical Centre, Leiden, The Netherlands.
authors.forename: Amina Fas
authors.initials: AF
authors.lastname: Teunisse
authors.affiliation: Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.
authors.forename: Atara
authors.initials: A
authors.lastname: Posner
authors.affiliation: Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.
authors.forename: Tahlia
authors.initials: T
authors.lastname: Procter
authors.affiliation: Molecular Genetics of Cancer, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Herold
authors.affiliation: Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.
authors.forename: Cristina
authors.identifier: 0000-0003-0720-2652
authors.initials: C
authors.lastname: Gamell
authors.affiliation: Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium.|Laboratory for Molecular Cancer Biology, Department of Oncology, KULeuven, Leuven, Belgium.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marine
authors.affiliation: Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
authors.affiliation: Department of Molecular Cell Biology, University Medical Centre, Leiden, The Netherlands.
authors.forename: Aart
authors.initials: A
authors.lastname: Jochemsen
authors.affiliation: Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.
authors.forename: Sue
authors.identifier: 0000-0003-2484-1712
authors.initials: S
authors.lastname: Haupt
authors.affiliation: 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.
authors.forename: Ygal
authors.identifier: 0000-0001-5925-0096
authors.initials: Y
authors.lastname: Haupt
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D063646:Carcinogenesis / Q000235:genetics; D018797:Cell Cycle Proteins; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C568282:(10-methyl-9-anthryl)methyl imidothiocarbamate; D000873:Anthracenes; D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D013890:Thiourea
keywords: MDM4; TNBC; breast cancer; mutant p53; p27