PMID- 28097652
OWN - NLM
STAT- MEDLINE
DCOM- 20170829
LR  - 20220321
IS  - 1096-9896 (Electronic)
IS  - 0022-3417 (Linking)
VI  - 241
IP  - 5
DP  - 2017 Apr
TI  - MDM4 is a rational target for treating breast cancers with mutant p53.
PG  - 661-670
LID - 10.1002/path.4877 [doi]
AB  - 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 (c) 2017 Pathological Society of Great Britain and Ireland. Published by 
      John Wiley & Sons, Ltd.
CI  - Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by 
      John Wiley & Sons, Ltd.
FAU - Miranda, Panimaya Jeffreena
AU  - Miranda PJ
AUID- ORCID: 0000-0002-1404-0754
AD  - Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, 
      Victoria, Australia.
AD  - The Sir Peter MacCallum Department of Oncology, The University of Melbourne, 
      Victoria, Australia.
FAU - Buckley, Daniel
AU  - Buckley D
AD  - Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, 
      Victoria, Australia.
AD  - The Sir Peter MacCallum Department of Oncology, The University of Melbourne, 
      Victoria, Australia.
FAU - Raghu, Dinesh
AU  - Raghu D
AD  - Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, 
      Victoria, Australia.
AD  - The Sir Peter MacCallum Department of Oncology, The University of Melbourne, 
      Victoria, Australia.
FAU - Pang, Jia-Min B
AU  - Pang JB
AD  - Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, 
      Victoria, Australia.
AD  - Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, 
      Australia.
FAU - Takano, Elena A
AU  - Takano EA
AD  - Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, 
      Victoria, Australia.
AD  - Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, 
      Australia.
FAU - Vijayakumaran, Reshma
AU  - Vijayakumaran R
AD  - Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, 
      Victoria, Australia.
AD  - The Sir Peter MacCallum Department of Oncology, The University of Melbourne, 
      Victoria, Australia.
FAU - Teunisse, Amina Fas
AU  - Teunisse AF
AD  - Department of Molecular Cell Biology, University Medical Centre, Leiden, The 
      Netherlands.
FAU - Posner, Atara
AU  - Posner A
AD  - Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, 
      Victoria, Australia.
AD  - The Sir Peter MacCallum Department of Oncology, The University of Melbourne, 
      Victoria, Australia.
FAU - Procter, Tahlia
AU  - Procter T
AD  - Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, 
      Victoria, Australia.
AD  - The Sir Peter MacCallum Department of Oncology, The University of Melbourne, 
      Victoria, Australia.
FAU - Herold, Marco J
AU  - Herold MJ
AD  - Molecular Genetics of Cancer, The Walter and Eliza Hall Institute, Parkville, 
      Victoria, Australia.
AD  - Department of Medical Biology, University of Melbourne, Parkville, Victoria, 
      Australia.
FAU - Gamell, Cristina
AU  - Gamell C
AUID- ORCID: 0000-0003-0720-2652
AD  - Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, 
      Victoria, Australia.
AD  - The Sir Peter MacCallum Department of Oncology, The University of Melbourne, 
      Victoria, Australia.
FAU - Marine, Jean-Christophe
AU  - Marine JC
AD  - Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, 
      Belgium.
AD  - Laboratory for Molecular Cancer Biology, Department of Oncology, KULeuven, 
      Leuven, Belgium.
FAU - Fox, Stephen B
AU  - Fox SB
AD  - Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, 
      Victoria, Australia.
AD  - Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, 
      Australia.
FAU - Jochemsen, Aart
AU  - Jochemsen A
AD  - Department of Molecular Cell Biology, University Medical Centre, Leiden, The 
      Netherlands.
FAU - Haupt, Sue
AU  - Haupt S
AUID- ORCID: 0000-0003-2484-1712
AD  - Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, 
      Victoria, Australia.
AD  - The Sir Peter MacCallum Department of Oncology, The University of Melbourne, 
      Victoria, Australia.
FAU - Haupt, Ygal
AU  - Haupt Y
AUID- ORCID: 0000-0001-5925-0096
AD  - Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, 
      Victoria, Australia.
AD  - The Sir Peter MacCallum Department of Oncology, The University of Melbourne, 
      Victoria, Australia.
AD  - Department of Pathology, The University of Melbourne, Parkville, Victoria, 
      Australia.
AD  - Department of Biochemistry and Molecular Biology, Monash University, Clayton, 
      Australia.
LA  - eng
PT  - Journal Article
DEP - 20170301
PL  - England
TA  - J Pathol
JT  - The Journal of pathology
JID - 0204634
RN  - 0 ((10-methyl-9-anthryl)methyl imidothiocarbamate)
RN  - 0 (Anthracenes)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (MDM4 protein, human)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - GYV9AM2QAG (Thiourea)
SB  - IM
MH  - Anthracenes/pharmacology
MH  - Carcinogenesis/genetics
MH  - Cell Cycle Proteins
MH  - Cell Line
MH  - Cell Proliferation
MH  - Female
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Mutation
MH  - Nuclear Proteins/antagonists & inhibitors/genetics/*metabolism
MH  - Proto-Oncogene Proteins/antagonists & inhibitors/genetics/*metabolism
MH  - Thiourea/analogs & derivatives/pharmacology
MH  - Triple Negative Breast Neoplasms/drug therapy/*genetics/pathology
MH  - Tumor Suppressor Protein p53/*genetics/metabolism
OTO - NOTNLM
OT  - MDM4
OT  - TNBC
OT  - breast cancer
OT  - mutant p53
OT  - p27
EDAT- 2017/01/18 06:00
MHDA- 2017/08/30 06:00
CRDT- 2017/01/19 06:00
PHST- 2016/08/19 00:00 [received]
PHST- 2016/12/20 00:00 [revised]
PHST- 2017/01/08 00:00 [accepted]
PHST- 2017/01/18 06:00 [pubmed]
PHST- 2017/08/30 06:00 [medline]
PHST- 2017/01/19 06:00 [entrez]
AID - 10.1002/path.4877 [doi]
PST - ppublish
SO  - J Pathol. 2017 Apr;241(5):661-670. doi: 10.1002/path.4877. Epub 2017 Mar 1.