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.

https://minerva-access.unimelb.edu.au/bitstream/handle/11343/261470/PMC4650725.pdf

Targeting Mdmx to treat breast cancers with wild-type p53

Background

Retinoblastoma (RB) accounts for 3% of all childhood malignancies, with different incidences around the world. This malignancy results from loss-of-function of both RB1 alleles although other genes, like MDM2 and MDM4, have been proposed to be involved in tumor development.



Procedure

We genotyped rs2279744T>G and rs937283A>G in MDM2, and rs4252668T>C and rs116197192G>A in MDM4, in 104 unrelated RB patients and 104 controls. Sixty-month survival Kaplan–Meier curves and χ2-tests were performed for estimating the putative effect of MDM2 and MDM4 alleles on disease progression and survival of RB patients.



Results

MDM2 rs2279744G was significantly more frequent in controls, indicating an apparently protective effect on RB development. However, survival of patients who carried a constitutional RB1 mutation was significantly lower with rs2279744TG or GG than with rs2279744TT. Presence of rs2279744G and a constitutional RB1 mutation was sixfold more frequent in the 0–12 month age group than other age groups at onset of symptoms (P = 0.0401). MDM4 rs4252668C was present at a significantly higher frequency in controls while the frequency of MDM4 rs116197192G was significantly higher in RB patients, suggesting that this allele might increase the risk of developing RB.



Conclusion

Our results indicate that MDM2 and MDM4 polymorphisms may influence development and/or survival in RB. Pediatr Blood Cancer 2012; 59: 39–43. © 2011 Wiley Periodicals, Inc.

Influence of MDM2 and MDM4 on development and survival in hereditary retinoblastoma

// Ming-Jie Wang 1, * , Yong-Jun Luo 2, * , Zhi-Yong Shi 3, * , Xiao-Liang Xu 4 , Guo-Liang Yao 5 , Rui-Ping Liu 1 , Hui Zhao 6 1 Department of Orthopedics, Affiliated Hospital of Nanjing Medical University, Changzhou Second People’s Hospital, Changzhou 213003, China 2 Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China 3 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases, Beijing 100050, China 4 Department of Liver Surgery of Jiangsu Province People's Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China 5 Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China 6 Department of General Surgery, Third Affiliated Hospital of Nantong University, Wuxi, 214000, China * These authors contributed equally to this work Correspondence to: Rui-Ping Liu, email: liuruiping216@sina.com Hui Zhao, email: hui_1007@163.com Keywords: MDM4, single nucleotide polymorphisms, meta-analysis, cancer Received: April 15, 2016      Accepted: July 10, 2016      Published: July 28, 2016 ABSTRACT Considerable studies have investigated the associations between MDM4 gene polymorphisms and cancer risk recently, but with contradictory results. The aim of this meta-analysis was to evaluate the associations between MDM4 gene polymorphisms and cancer risk. Relevant studies were identified by a systematic search of PubMed, Embase, and CNKI databases. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were used to describe the strength of the associations. Fifty-six studies published in 11 publications involving 18,910 cases and 51,609 controls were included in this meta-analysis. Five MDM4 gene polymorphisms were evaluated: rs4245739, rs1563828, rs11801299, rs10900598, and rs1380576. Our analyses suggested that the rs4245739 polymorphism was significantly associated with overall cancer risk. Furthermore, stratification analyses of ethnicity indicated that rs4245739 decreased the risk of cancer among the Asian population, and stratification analyses of smoking status indicated that rs4245739 decreased the risk of cancer among nonsmokers. However, stratification analyses of cancer type and sex suggested that rs4245739 was not related to cancer risk. There were no associations of rs1563828, rs11801299, rs10900598, or rs1380576 with overall cancer risk. In conclusion, our analyses indicated that rs4245739 polymorphism in the MDM4 gene may play an important role in the etiology of cancer.

/pdf/the-associations-between-mdm4-gene-polymorphisms-and-cancer-148zerwy4e.pdf

The associations between MDM4 gene polymorphisms and cancer risk.

// Chaoyi Xu 1, * , Jinhong Zhu 3, * , Wen Fu 2, * , Zongwen Liang 1 , Shujie Song 4 , Yuan Zhao 1 , Lihua Lyu 4 , Anqi Zhang 1 , Jing He 1, 2 , Ping Duan 1 1 Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou 325027, Zhejiang, China 2 Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China 3 Molecular Epidemiology Laboratory and Department of Laboratory Medicine, Harbin Medical University Cancer Hospital, Harbin 150040, Heilongjiang, China 4 Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China * These authors contributed equally to this work Correspondence to: Ping Duan, email: dppddpp@126.com Jing He, email: hejing198374@gmail.com Keywords: MDM4, polymorphism, cancer susceptibility, meta-analysis Received: June 15, 2016      Accepted: September 21, 2016      Published: September 28, 2016 ABSTRACT Mouse double minute 4 (MDM4) is a p53-interacting oncoprotein that plays an important role in the p53 tumor suppressor pathway. The common rs4245739 A > C polymorphism creates a miR-191 binding site in the MDM4 gene transcript. Numerous studies have investigated the association between this MDM4 polymorphism and cancer risk, but have failed to reach a definitive conclusion. To address this issue, we conducted a meta-analysis by selecting eligible studies from MEDLINE, EMBASE, and Chinese Biomedical databases. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. We also performed genotype-based mRNA expression analysis using data from 270 individuals retrieved from public datasets. A total of 15 studies with 19796 cases and 49681 controls were included in the final meta-analysis. The pooled results revealed that the MDM4 rs4245739C allele is associated with a decreased cancer risk in the heterozygous (AC vs. AA: OR = 0.82, 95% CI = 0.73−0.93), dominant (AC/CC vs. AA: OR = 0.82, 95% CI = 0.72−0.93), and allele contrast models (C vs. A: OR = 0.84, 95% CI = 0.76−0.94). The association was more prominent in Asians and population-based studies. We also found that the rs4245739C allele was associated with decreased MDM4 mRNA expression, especially for Caucasians. Thus the MDM4 rs4245739 A > C polymorphism appears to be associated with decreased cancer risk. These findings would be strengthened by new studies with larger sample sizes and encompassing additional ethnicities.

/pdf/mdm4-rs4245739-a-c-polymorphism-correlates-with-reduced-qa0ihu4nzu.pdf

MDM4 rs4245739 A > C polymorphism correlates with reduced overall cancer risk in a meta-analysis of 69477 subjects

Weaver gene plays an essential physiological role in the function of many organs, including brain, heart, kidney and endocrine cells, and also in the regulation of insulin secretion by glucose and/or neurotransmitters. Thus, weaver gene is an important potential candidate gene effecting on performance traits. The objective of this study was to detect the genetic variation of five loci within weaver gene by PCR-SSCP, DNA sequencing and forced PCR-RFLP methods in 1,019 Chinese indigenous goats. Two novel coding SNPs (XM_598993:m.864G>A; XM_598993:m.1224T>A) locating on P3 and P4 loci were identified and detected by MluI and AsuII forced PCR-RFLP, respectively. In the MluI analysis, the frequencies of goat MluI-A allele in the analyzed populations were 0.226, 0.248, 0.096 and 0.088 for XNSN, GZ, SBWC and XJWC, respectively. Genotypic frequencies were found to be significantly different in four breeds (χ2 = 75.842, df = 6, P < 0.001); In the AsuII analysis, the frequencies of goat AsuII-A allele in the analyzed populations were 0.584, 0.441, 0.073 and 0.063 for XNSN, GZ, SBWC and XJWC, respectively. Genotypic frequencies were found to be significantly different among four breeds (χ2 = 399.464, df = 6, P < 0.001). The frequencies of allele MluI-A and AsuII-A in XNSN and GZ populations were significantly higher than those of SBWC and XJWC goats. Association analysis with adjusted milk yield in the XNSN breed indicated that the animals with AsuII-AA genotype owned significantly higher adjusted milk yield than the ones with AsuII-TT genotype in the second lactation (P < 0.05). The observation suggested that the allele “AsuII-A” had the positive effects on adjusted milk yield in the second lactation.

Two novel cSNPs of weaver gene in Chinese indigenous goat and their associations with milk yield

MDM4 is a negative regulator of p53 and cooperates with MDM2 in the cellular response to DNA damage. It is unknown, however, whether MDM4 gene alterations play some role in the inherited component of breast cancer susceptibility. We sequenced the whole MDM4 coding region and flanking untranslated regions in genomic DNA samples obtained from 40 German patients with familial breast cancer. Selected variants were subsequently screened by RFLP-based assays in an extended set of breast cancer cases and controls. Our resequencing study uncovered two MDM4 coding variants in 4/40 patients. Three patients carried a silent substitution at codon 74 that was linked with another rare variant in the 5'UTR. No association of this allele with breast cancer was found in a subsequent screening of 133 patients with bilateral breast cancer and 136 controls. The fourth patient was heterozygous for the missense substitution D153G which is located in a less conserved region of the MDM4 protein but may affect a predicted phosphorylation site. The D153G substitution only partially segregated with breast cancer in the family and was not identified on additional 680 chromosomes screened. This study did not reveal clearly pathogenic mutations although it uncovered two new unclassified variants at a low frequency. We conclude that there is no evidence for a major role of MDM4 coding variants in the inherited susceptibility towards breast cancer in German patients.

/pdf/mutation-analysis-of-the-mdm4-gene-in-german-breast-cancer-46p4tidin4.pdf

Lina Govbakh

Papers

Mutation analysis of the MDM4 gene in German breast cancer patients.