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.

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

“…High MDM4 levels were found to be a feature of WT p53 BCs, as demonstrated in luminal subtypes. Basal‐like biopsies in our mixed BC subtype tissue microarray (TMA) also stained intensely for p53, which is generally indicative of p53 mutations, coincident with high MDM4 levels . To expand this finding, a TMA of 87 biopsies derived from basal‐like BC (the majority of which have a TNBC phenotype ) was stained by IHC for p53 and MDM4 (Figure ).…”

“…Our study shows strategic vulnerability in the dependency of BC with mutant p53 on the expression of MDM4, a key negative regulator of p53. We have recently reported that MDM4 is highly expressed in a large proportion of luminal BCs, which mainly have WT p53 . This high expression of MDM4 can be rationalized in BCs expressing WT p53.…”

The DNA Damage Transducer RNF8 Facilitates Cancer Chemoresistance and Progression through Twist Activation

“…It is noteworthy that our research uncovers several E3 ligases, such as PML FBXO5, MALT1 and MDM4, as potential EMT regulators despite their TNBC- associated gene mutations are not as common as RNF8 (Figure S1C). FBXO5 (also known as FBX5 and Emi1), MALT1 and MDM4 have been reported as therapeutic targets for breast cancer (Haupt et al, 2015; Pan et al, 2016; Wang et al, 2014). Even though PML is a legitimate tumor suppressor in leukemia, it has been shown to be upregulated in breast cancer in which PML facilitates fatty acid metabolism to support breast cancer survival (Carracedo et al, 2012).…”

CITED2 in breast carcinoma as a potent prognostic predictor associated with proliferation, migration and chemoresistance

“…). Because DNA damage induces p53 protein accumulation and p53‐dependent apoptosis, we next examined the possible regulation of p53 expression by CITED2 under chemotherapy in MCF‐7 cells with wild‐type p53 …”