title: 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=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=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 (P<0.0001) 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=1.35, P=0.02) in a Cox regression model including MDM2 expression, tumour grade, nodal status, ER status and tumour size. Immunohistochemical studies of MDM2 in more than 2000 breast carcinomas show that MDM2 is an independent negative prognostic marker.
authors.affiliation: Genetic Pathology Evaluation Centre of the Department of Pathology, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC, Canada.
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Turbin
authors.forename: Maggie C U
authors.initials: MC
authors.lastname: Cheang
authors.forename: Chris D
authors.initials: CD
authors.lastname: Bajdik
authors.forename: Karen A
authors.initials: KA
authors.lastname: Gelmon
authors.forename: Erika
authors.initials: E
authors.lastname: Yorida
authors.forename: Alessandro
authors.initials: A
authors.lastname: De Luca
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D019927:Cyclin E / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods / Q000706:statistics & numerical data; D053555:Keratin-5; D053553:Keratin-6; D007633:Keratins / Q000032:analysis; D019394:Ki-67 Antigen / Q000032:analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D015203:Reproducibility of Results; D016019:Survival Analysis; D046888:Tissue Array Analysis / Q000379:methods / Q000706:statistics & numerical data; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; D019927:Cyclin E; D053555:Keratin-5; D053553:Keratin-6; D007633:Keratins; D019394:Ki-67 Antigen; D051736:Proto-Oncogene Proteins c-mdm2; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; C503940:KRT5 protein, human; C507569:KRT6A protein, human; C507570:KRT6B protein, human; C507571:KRT6C protein, human