title: Targeting Mdmx to treat breast cancers with wild-type p53.
abstract: The function of the tumor suppressor p53 is universally compromised in cancers. It is the most frequently mutated gene in human cancers (reviewed). In cases where p53 is not mutated, alternative regulatory pathways inactivate its tumor suppressive functions. This is primarily achieved through elevation in the expression of the key inhibitors of p53: Mdm2 or Mdmx (also called Mdm4) (reviewed). In breast cancer (BrCa), the frequency of p53 mutations varies markedly between the different subtypes, with basal-like BrCas bearing a high frequency of p53 mutations, whereas luminal BrCas generally express wild-type (wt) p53. Here we show that Mdmx is unexpectedly highly expressed in normal breast epithelial cells and its expression is further elevated in most luminal BrCas, whereas p53 expression is generally low, consistent with wt p53 status. Inducible knockdown (KD) of Mdmx in luminal BrCa MCF-7 cells impedes the growth of these cells in culture, in a p53-dependent manner. Importantly, KD of Mdmx in orthotopic xenograft transplants resulted in growth inhibition associated with prolonged survival, both in a preventative model and also in a treatment model. Growth impediment in response to Mdmx KD was associated with cellular senescence. The growth inhibitory capacity of Mdmx KD was recapitulated in an additional luminal BrCa cell line MPE600, which expresses wt p53. Further, the growth inhibitory capacity of Mdmx KD was also demonstrated in the wt p53 basal-like cell line SKBR7 line. These results identify Mdmx growth dependency in wt p53 expressing BrCas, across a range of subtypes. Based on our findings, we propose that Mdmx targeting is an attractive strategy for treating BrCas harboring wt p53.
authors.affiliation: Tumor Suppression Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Haupt
authors.affiliation: Tumor Suppression Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Buckley
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: J-M B
authors.initials: JM
authors.lastname: Pang
authors.affiliation: Tumor Suppression Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Panimaya
authors.affiliation: Tumor Suppression Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: P J
authors.initials: PJ
authors.lastname: Paul
authors.affiliation: Tumor Suppression Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Gamell
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: E A
authors.initials: EA
authors.lastname: Takano
authors.affiliation: Tumor Suppression Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Y Ying
authors.initials: YY
authors.lastname: Lee
authors.affiliation: Tumor Suppression Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Hiddingh
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: T-M
authors.initials: TM
authors.lastname: Rogers
authors.affiliation: Department of Molecular Cell Biology, University Medical Centre, Leiden, The Netherlands.
authors.forename: A F A S
authors.initials: AF
authors.lastname: Teunisse
authors.affiliation: 1] Department of Molecular Genetics of Cancer, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Herold
authors.affiliation: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: J-C
authors.initials: JC
authors.lastname: Marine
authors.affiliation: 1] Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia [2] Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: S B
authors.initials: SB
authors.lastname: Fox
authors.affiliation: Department of Molecular Cell Biology, University Medical Centre, Leiden, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Jochemsen
authors.affiliation: 1] Tumor Suppression Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia [2] Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia [3] Department of Pathology, University of Melbourne, Parkville, Victoria, Australia [4] Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Haupt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53