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.

Targeting MDMX and PKCδ to improve current uveal melanoma therapeutic strategies

“…We demonstrate here that depletion of MDMX also enhanced the growth inhibitory effects of PKC inhibition. Furthermore, we have shown previously that MDMX has oncogenic effects beyond inhibition of p53 12 , 19 , 22 , 23 , so targeting MDMX might have more wide-ranging tumor growth inhibitory effects than merely p53 reactivation.…”

A novel logistic regression model combining semi-supervised learning and active learning for disease classification

“…These genes are shown in bold in the Tables 6 – 9 . The MDM4 in DLBCL plays a very important role in the proliferation of the cancer cells, and it is crucial for the establishment and progression of tumors 24 . JUNB plays a specific role in cancer cell proliferation, survival and drug resistance 25 .…”

Mutant TP53 modulates metastasis of triple negative breast cancer through adenosine A2b receptor signaling

“…Many cancers express mutant p53 proteins that have lost wild-type tumor suppressor activity and/or have acquired additional oncogenic functions that contribute to tumor progression. Indeed, mutation of TP53 defines a key step in the progression towards aggressive and metastatic breast cancer with the poorest outcome [ 5 ]. The structural changes introduced by five hot-spot mutations (V143A, G245S, R248Q, R249S, and R273H) in TP53 have been evaluated by chemical-shift changes.…”

“…The identification of genes that have synthetic lethality with mutant TP53 is a promising approach in this regard, since TP53 mutations occur in approximately 40% percent of all breast cancers, with the highest frequency found in the basal-like (80%) and HER-2-enriched (72%) subtypes of TNBC, and the lowest found in the Luminal A (12%) and Luminal B (29%) subtypes [ 3 , 4 ]. Breast cancers carrying mutations in TP53 are characterized by an aggressive and metastatic phenotype with the poorest outcomes [ 5 ]. Mutations at five known hot-spots in TP53 (V143A, G245S, R248Q, R249S and R273H) are frequently associated with gain-of-function (GOF) phenotypes [ 6 ], although it is the loss of p53 function that is more generally considered to play an essential role in carcinogenesis and disease progression [ 7 , 8 ].…”