An observational study on the expression levels of MDM2 and MDMX proteins, and associated effects on P53 in a series of human liposarcomas

Abstract

BackgroundInactivation of wild type P53 by its main cellular inhibitors (MDM2 and MDMX) is a well recognised feature of tumour formation in liposarcomas. MDM2 over-expression has been detected in approximately 80% of liposarcomas but only limited information is available about MDMX over-expression. To date, we are not aware of any study that has described the patterns of MDM2 and MDMX co-expression in liposarcomas. Such information has become more pertinent as various novel MDM2 and/or MDMX single and dual affinity antagonist compounds are emerging as an alternative approach for potential targeted therapeutic strategies.MethodsWe analysed a case series of 61 fully characterized liposarcomas of various sub-types by immunohistochemistry, to assess the expression levels of P53, MDM2 and MDMX, simultaneously. P53 sequencing was performed in all cases that expressed P53 protein in 10% or more of cells to rule out mutation-related over-expression.Results50 cases over-expressed MDM2 and 42 of these co-expressed MDMX at varying relative levels. The relative expression levels of the two proteins with respect to each other were subtype-dependent. This apparently affected the detected levels of P53 directly in two distinct patterns. Diminished levels of P53 were observed when MDM2 was significantly higher in relation to MDMX, suggesting a dominant role for MDM2 in the degradation of P53. Higher levels of P53 were noted with increasing MDMX levels suggesting an interaction between MDM2 and MDMX that resulted in a reduced efficiency of MDM2 in degrading P53. Of the 26 cases of liposarcoma with elevated P53 expression, 5 were found to have a somatic mutation in the P53 gene.ConclusionsThe results suggest that complex dynamic interactions between MDM2 and MDMX proteins may directly affect the cellular levels of P53. This therefore suggests that careful characterization of both these markers will be necessary in tumours when considering in vivo evaluation of novel blocker compounds for MDM proteins, as a therapeutic strategy to restore wild type P53 function.

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XI-006 induces potent p53-independent apoptosis in Ewing sarcoma

“…MDM4 immunohistochemical protocol was adapted from 54 . Briefly, FFPE (4 μm thickness) were deparaffinised by serial immersion in a xylene-to-ethanol solvent gradient.…”

The Value of MRI in Distinguishing Subtypes of Lipomatous Extremity Tumors Needs Reassessment in the Era of MDM2 and CDK4 Testing

“…Liposarcomas represent approximately 20% of all soft tissue sarcomas and are divided into various subtypes including atypical lipomatous tumors/well-differentiated liposarcomas (ALT/WDLs), de-differentiated liposarcoma, myxoid liposarcoma, round cell liposarcomas, and pleomorphic liposarcomas. ALT/WDLs are often difficult to distinguish from benign lipomas on MRI [ 1 , 2 , 6 , 9 , 10 ] and have different treatments as well as prognosis. On MRI, ALT/WDLs are known for having thick septa, lack of capsule with less well-defined margins, nodularity, internal cystic changes, heterogeneity, and enhancement on T2-weighted imaging.…”