Amplification of Mdmx and overexpression of MDM2 contribute to mammary carcinogenesis by substituting for p53 mutations

Diagnostic Pathology

Li Li¹  Yan Wang¹  Xiaojuan Wu¹  Qingyong Meng²  Zhishuang Li¹  Kun Mu¹  Yan Li³  Qiong Yu¹ 

[1] Department of Pathology, Shandong University School of Medicine, 44#,Wenhua Xi Road, 250012 Jinan, Shandong, PR. China;The No.2 People’s Hospital of Jinan, 148#, Jingyi Road, 250001 Jinan, Shandong, People’s Republic of China;Department of Medical Oncology, Shandong Cancer Hospital and Institute, Jinan University, 250117 Jinan, Shandong, PR. China

关键词: FISH;    Mdm2;    Mdmx;    p53;    Breast cancer;   

Others  :  802063
DOI  :  10.1186/1746-1596-9-71

 received in 2014-01-16, accepted in 2014-03-18,  发布年份 2014

【 摘 要 】

Background

The p53 tumor suppressor gene is mutated or deleted in nearly half of human cancers. The murine double minute 2 (Mdm2) and Mdmx represent two important cellular regulators of p53. The aim of this study was to evaluate the abnormalities of p53, Mdmx and Mdm2 genes in archived breast cancers.

Methods

We assessed the genetic instability at p53, Mdmx and Mdm2 using high resolution multi-color fluorescent in situ hybridization (FISH) protocol and detected the expression status of the tumor protein p53 (TP53), MDMx and MDM2 by immunohistochemistry in 115 archived samples of infiltrating ductal breast carcinomas with foci of ductal carcinoma in situ (DCIS) components.

Results

The presence of p53 allelic loss and/or TP53 overexpression was observed in 38% out of all patients, and was significantly more often in larger, high grade, ER negative and high ki67 tumors. Mdmx amplification with low-level increase of gene copy number is at high frequency while Mdm2 amplification is rare in primary breast cancer. Mdmx amplification was seen in more invasive carcinomas than preinvasive lesions. MDMx and MDM2 overexpression were detected in 65% and 38% of all cases respectively. Moreover it was showed that most tumors contained either p53 dysfunction or Mdm2 alteration, but not both. This distribution was significant (P < 0.05). Inverse correlation between Mdmx amplification/overexpression and p53 disfunction was also observed (P < 0.05).

Conclusions

Our results suggest the involvement of Mdm2 and Mdmx in p53-independent breast carcinogenesis and Mdmx may contribute to the regulation of p53 independently of Mdm2.

Virtual slides

The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1450529994118798 webcite.

【 授权许可】

   
2014 Yu et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Harris SL, Levine AJ: The p53 pathway: positive and negative feedback loops. Oncogene 2005, 24:2899-2908.
• [2]Liu G, Chen X: Regulation of the p53 transcriptional activity. J Cell Biochem 2006, 97:448-458.
• [3]Wade M, Li YC, Wahl GM: MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 2013, 13:83-96.
• [4]Shadfan M, Lopez-Pajares V, Yuan ZM: MDM2 And MDMX: alone and together in regulation of p53. Transl Cancer Res 2012, 1:88-89.
• [5]Deng G, Chen LC, Schott DR, Thor A, Bhargava V, Ljung BM, Chew K, Smith HS: Loss of heterozygosity and p53 gene mutations in breast cancer. Cancer Res 1994, 54:499-505.
• [6]Pei D, Zhang Y, Zheng J: Regulation of p53: a collaboration between Mdm2 and Mdmx. Oncotarget 2012, 23:228-235.
• [7]Done SJ, Arneson CR, Ozçelik H, Redston M, Andrulis IL: P53 protein accumulation in non-invasive lesions surrounding p53 mutation positive invasive breast cancers. Breast Cancer Res Treat 2011, 65:111-118.
• [8]Cahilly-Snyder L, Yang-Feng T, Francke U, George DL: Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line. Somat Cell Mol Genet1 1987, 3:235-244.
• [9]Momand J, Jung D, Wilczynski S, Niland J: The MDM2 gene amplification database. Nucleic Acids Res 1998, 26:3453-3459.
• [10]Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B: Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 1992, 358:80-83.
• [11]Veerakumarasivam A, Scott HE, Chin SF, Warren A, Wallard MJ, Grimmer D, Ichimura K, Caldas C, Collins VP, Neal DE, Kelly JD: High-resolution array-based comparative genomic hybridization of bladder cancers identifies mouse double minute 4 (MDM4) as an amplification target exclusive of MDM2 and TP53. Clin Cancer Res 2008, 14:2527-2534.
• [12]Shvarts A, Bazuine M, Dekker P, Ramos YF, Steegenga WT, Merckx G, van Ham RC, van der Houven van Oordt W, van der EbA J, Jochemsen AG: Isolation and identification of the human homolog of a new p53-binding protein, Mdmx. Genomics 1997, 43:34-42.
• [13]Laurie NA, Donovan SL, Shih CS, Zhang J, Mills N, Fuller C, Teunisse A, Lam S, Ramos Y, Mohan A, Johnson D, Wilson M, Rodriguez-Galindo C, Quarto M, Francoz S, Mendrysa SM, Guy RK, Marine JC, Jochemsen AG, Dyer MA: Inactivation of the p53 pathway in retinoblastoma. Nature 2006, 444:61-66.
• [14]Riemenschneider MJ, Buschges R, Wolter M, Reifenberger J, Bostrom J, Kraus JA, Schlegel U, Reifenberger GH: Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification. Cancer Res 1999, 59:6091-6096.
• [15]Danovi D, Meulmeester E, Pasini D, Migliorini D, Capra M, Frenk R, de Graaf P, Francoz S, Gasparini P, Gobbi A, Helin K, Pelicci PG, Joechemsen AG, Marine JC: Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Mol Cell Biol 2004, 24:5835-5843.
• [16]Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ: WHO classification of tumors of the breast. 4th edition. Lyon: IARC Press; 2012:33-38.
• [17]Li L, Mu K, Zhou G, Lan L, Auer G, Zetterberg A: Genomic instability and proliferative activity as risk factors for distant metastases in breast cancer. Br J Cancer 2008, 99:513-519.
• [18]Kikuchi S, Nishimura R, Osako T, Okumura Y, Nishiyama Y, Toyozumi Y, Arima N: Definition of p53 overexpression and its association with the clinicopathological features in luminal/HER2-negative breast cancer. Anticancer Res 2013, 33:3891-3897.
• [19]Alsner J, Jensen V, Kyndi M, Offersen BV, Vu P, Børresen-Dale AL, Overgaard JA: Comparison between p53 accumulation determined by immunohistochemistry and TP53 mutations as prognostic variables in tumours from breast cancer patients. Acta Oncol 2008, 47:600-607.
• [20]Ahlin C, Aaltonen K, Amini RM, Nevanlinna H, Fjallskog ML, Blomqvist C: Ki67 and cyclin A as prognostic factors in early breast cancer. What are the optimal cut-off values? Histopathology 2007, 51:491-498.
• [21]Matsuyama H, Pan Y, Mahdy EA, Malmstrom PU, Hedrum A, Uhlen M, Busch C, Hirano T, Auer G, Tribukait B, Naito K, Lichter P, Ekman P, Bergerheim US: p53 deletion as a genetic marker in urothelial tumor by fluorescence in situ hybridization. Cancer Res 1994, 54:6057-6060.
• [22]Levine AJ, Momand J, Finlay CAM: The p53 tumour suppressor gene. Nature 1991, 351:453-456.
• [23]Preat F, Simon P, Noel JC: Differences in breast carcinoma immunohistochemical subtypes between immigrant Arab and European women. Diagn Pathol 2014, 9:26-30. BioMed Central Full Text
• [24]Guo L, Meng J, Yilamu D, Jakulin A, Fu M, Wang B, Abulajiang G: Significance of ERβ expression in different molecular subtypes of breast cancer. Diagn Pathol 2014, 9:20-25. BioMed Central Full Text
• [25]Zhang Q, Zhang Q, Cong H, Zhang X: The ectopic expression of BRCA1 is associated with genesis, progression, and prognosis of breast cancer in young patients. Diagn Pathol 2012, 7:181-187. BioMed Central Full Text
• [26]Cheng H, Qin Y, Fan H, Su P, Zhang X, Zhang H, Zhou G: Overexpression of CARM1 in breast cancer is correlated with poorly characterized clinicopathologic parameters and molecular subtypes. Diagn Pathol 2013, 8:129-137. BioMed Central Full Text
• [27]Liu L, Liu Z, Qu S, Zheng Z, Liu Y, Xie X, Song F: Small breast epithelial mucin tumor tissue expression is associated with increased risk of recurrence and death in triple-negative breast cancer patients. Diagn Pathol 2013, 8:71-80. BioMed Central Full Text
• [28]Wang S, Li H, Wang J, Wang D: Expression of microRNA-497 and its prognostic significance in human breast cancer. Diagn Pathol 2013, 8(1):172-178. BioMed Central Full Text
• [29]Varley J, Brammar W, Lane D, Swallow J, Dolan C, Walker R: Loss of chromosome 17p13 sequences and mutation of p53 in human breast carcinomas. Oncogene 1991, 6:413-421.
• [30]Eyfjörd JE, Thorlacius S, Steinarsdottir M, Valgardsdottir R, Ogmundsdottir HM, Anamthawat-Jonsson K: p53 abnormalities and genomic instability in primary human breast carcinomas. Cancer Res 1995, 55:646-651.
• [31]Gursan N, Karakök M, Sari I, Gursan MS: The relationship between expression of p53/Bcl-2 and histopathological criteria in breast invasive ductal carcinomas. Int J Clin Pract 2001, 55:589-590.
• [32]Pratap R, Shousha S: Breast carcinoma in women under the age of 50: Relationship between p53 immunostaining, tumour grade, and axillary lymph node status. Breast Cancer Res Treat 1998, 49:35-39.
• [33]Nag S, Qin J, Srivenugopal KS, Wang M, Zhang R: The MDM2-p53 pathway revisited. PLoS One 2013, 27(4):254-271.
• [34]McCann AH, Kirley A, Carney DN, Corbally N, Magee HM, Keating G, Dervan PA: Amplification of the MDM2 gene in human breast cancer and its association with MDM2 and p53 protein status. Br J Cancer 1995, 71:981-985.
• [35]Deb SP: Cell cycle regulatory functions of the human oncoprotein MDM2. Mol Cancer Res 2003, 1:1009-1016.
• [36]Knappskog S, Lønning PE: P53 and its molecular basis to chemoresistance in breast cancer. Expert Opin Ther Targets 2012, 16(Suppl 1):S23-S30.
• [37]Marine JC, Dyer MA, Jochemsen AG: MDMX: from bench to bedside. J Cell Sci 2007, 20:371-378.
• [38]Migliorini D, Lazzerini Denchi E, Danovi D, Jochemsen A, Capillo M, Gobbi A, Helin K, Pelicci PG, Marine JC: Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development. Mol Cell Biol 2002, 22:5527-5538.
• [39]Matijasevic Z, Krzywicka-Racka A, Sluder G, Jones SN: MdmX regulates transformation and chromosomal stability in p53-deficient cells. Cell Cycle 2008, 7:2967-2973.