MDM2 protein expression is a negative prognostic marker in breast carcinoma

Abstract

The protein encoded by the MDM2 oncogene inhibits the function of p53, leading to increased cell growth, avoidance of apoptosis, tolerance of genetic instability, and resistance to chemotherapy. The present study was performed to evaluate the relationship between MDM2 protein expression and survival in breast carcinoma. Two series of cases were used in this study: the first to identify the cutoff to be used in the interpretation of MDM2 immunostaining and perform preliminary survival analysis, and a second, independent series, to validate the findings from the first series and to perform multivariate analysis. For both series, archival sections of tissue microarrays were stained with anti-MDM2 antibody (NeoMarkers, Fremont, CA, USA) and MDM2 staining intensity was scored semiquantitatively. In the first series, 49 of 362 (14%) interpretable cases were positive for MDM2 expression, with 35 (10%) showing weak positivity and 14 (4%) strong positivity. Patients with MDM2-positive tumours had a significantly worse disease-specific survival than patients with MDM2-negative tumours (P ¼ 0.0022, 10-year DSS 61% (95% CI: 45-73) vs 73% (95% CI: 67-77)). No significant difference in survival was observed between patients with strongly and weakly MDM2-positive tumours (P ¼ 0.3). Accordingly, in the independent validation series weak and strong MDM2 positivity were combined and considered to be MDM2 positive. MDM2 expression was seen in 230/1747 (13%) interpretable cases in this series, with a significant difference (Po0.0001) in DSS between MDM2-negative and MDM2-positive cases (10 year DSS 58% (95% CI: 51-64) vs 73% (95% CI: 70-75)). MDM2 was an independent prognostic marker (HR ¼ The human MDM2 gene encodes a 491 amino-acid protein that contains a binding domain for the tumour suppressor p53. 1 This 90 kDa nuclear phosphoprotein can form a complex with both mutant and wild-type p53, 2 and takes part in downregulation of p53 functions, promoting the rapid degradation of p53 via a ubiquitin-proteasome pathway. 3-5 MDM2 protein acts as a nuclear-cytoplasmic transporter for the p53 protein. 5 The MDM2 gene is transcriptionally upregulated by p53 5-7 and acts as an oncogene in tissue culture. 5 In human tumours, MDM2 takes part in tumorigenesis through one of the three possible mechanisms: gene amplification, increased transcription or enhanced translation. 5 Overexpression of MDM2 is described in many human cancers, including breast carcinoma. 1,3,8 Overexpression of MDM2 protein correlates with high grade and was found to be an independent negative prognostic marker in human breast cancer in one study. 9 Other investigators observed that MDM2 overexpression correlates with favourable prognostic parameters such as ER overexpression. 10 Studies of MDM2 protein expression in breast carcinoma and its prognostic significance have been based on a limited number of cases, and the results of these studies have been inconsistent, as mentioned above. MDM2 amplification in breast1

Gene expression meta-analysis identifies chromosomal regions and candidate genes involved in breast cancer metastasis

“…In breast cancer expression of MDM2 at protein level is related to survival [37]. Our results clearly demonstrate a relation between amplification of 12q and poor prognosis in breast cancer although no genes fulfill criteria for additional regulation.…”

Impaired p53 function leads to centrosome amplification, acquired ERα phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts

“…This suggests the intriguing possibility that triple negative breast carcinomas may derive from early stage ERa þ tumors that development of centrosome amplification due to abrogated of p53 function. In addition, vMCF-7 DNP53 xenografts overexpress the oncoprotein Mdm2, which has been demonstrated to induce ER degradation and is associated with an aggressive phenotype (Kinyamu and Archer, 2003;Turbin et al, 2006). A recent study by Duong et al (2007) demonstrated that Mdm2 ubiquitin ligase activity degrades the ERa protein and thus downregulates ERa expression.…”

MDM2 Promoter SNP309 Is Associated with the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C

“…A T-to-G substitution in this region increases the binding affinity of the transcriptional activator Sp1, which results in high levels of MDM2 RNA and protein (24,29). The heightened MDM2 levels are poor prognostic factors in many human cancers, including lung cancers and breast cancers (30,31). MDM2 is a key negative regulator of p53, the most important tumor suppressor (32,33), which targets p53 for proteosomal degradation (33 -35).…”