MDM 2 and Prognosis

The cellular stress response pathway regulated by the p53 tumor suppressor is critical to the maintenance of genomic integrity and to the prevention of oncogenic transformation. Intracellular levels of p53 are tightly regulated by an autoregulatory feedback loop comprised of p53 and MDM2. It might be predicted that disruption of this loop, either through p53 mutation or overexpression of MDM2, would be a negative prognostic marker for cancer development, likelihood of relapse, or response to therapy. In fact, although MDM2 overexpression is common in cancer, it can be both a positive and a negative predictor of outcome in different tumors, and its significance as a biomarker remains controversial. Data from a number of different tumor types are reviewed for the predictive significance of MDM2 expression, along with evidence for different mechanisms of MDM2 overexpression in these different tumors. In light of the biological complexities underlying the p53-MDM2 loop, it is, perhaps, not surprising that no simple paradigm exists that is generally applicable. Much work remains to be done to elucidate the basic mechanisms underlying the physical interactions between the two proteins, the role of protein modifications in altering those interactions, and also the genetic and transcriptional deregulations by which protein levels are altered in human cancers. Only in this way will truly biologically relevant predictive factors emerge. Introduction The p53 tumor suppressor is central to the process by which a cell senses and responds to a variety of potentially oncogenic stresses, and it thereby prevents a damaged and potentially malignant cell from developing into a full-blown cancer. When exposed to stress such as DNA damage, different signal transduction pathways are activated, resulting in modifications of thep53protein.Thesestabilizep53, and intracellular levels rise. At thesametime, theyactivatep53asa transcriptionfactor. It, then, directs stress-specific transcriptional response programs, leading to growth arrest, senescence, or apoptosis (1, 2). Underscoring the critical role of p53 to this process is the observation that it is mutated in approximately half of all cases of cancer. p53 not only induces these response programs, but it also tightly regulates its own intracellular level through an autoregulatory feedback loop with MDM2. Activated p53 induces the transcription of MDM2, which binds to p53 and inactivates it, and which functions as an ubiquitin E3 ligase to target p53 to the proteosome for destruction (3). As a negative regulator of p53, it might be predicted that MDM2 is a proto-oncogene, and that overexpression of MDM2 would be oncogenic by preventing the accumulation of activated p53. Indeed, there is considerable evidence to support this hypothesis. Mice overexpressing Mdm2, for example, develop tumors at an increased rate, in particular, tumors commonly seen in transgenic mice with mutant p53, such as thymic lymphomas and sarcomas (4). In humans, overexpression of MDM2 is common in a variety of different tumor types (5). In many different tumor types, the loss of p53 is a poor prognostic marker. Likewise, as the functional equivalent of the loss of p53, the prediction is that MDM2 overexpression also correlates with poor prognosis, and can be a useful prognostic tool. The purpose of this review is to examine and summarize data from different human tumors in which it has been attempted to translate this prediction into the clinical realm. A goal of cancer biology is the identification of biomarkers predictive of disease or therapeutic response. Cancer is a complex disease, however, resulting from the deregulation of diverse interacting pathways. Translational studies, in which it is attempted to link alterations in simple biomarkers with distinct disease phenotypes, must be interpreted with caution. Although overexpression of MDM2 is common in cancer, its value as a prognosticmarker remains unclear, depending on tumor type, tissue of origin, and other factors. Indeed, whereasMDM2overexpression does correlate with poor prognosis in some tumors, a paradox is that it correlates with good prognosis in others. The major theme of this review is that a simple and reductionist approach to the interpretation of a single biomarker in tumors is unrealistic and often misleading. Several different tumors types will be used as examples to point out the difficulties inherent in attempting to extrapolate interpretations of very complex biological pathways and systems from simple markers. As will also become clear throughout this review, MDM2 itself presents unique challenges that limit its utility at present as a Received 5/15/03; revised 10/1/03; accepted 12/11/03. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Carlos Cordon-Cardo, Division of Molecular Pathology, Room S-801A, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-7746; Fax: (212) 794-3186. E-mail: cordon-c@mskcc.org Copyright D 2004 American Association for Cancer Research. The abbreviations used are MDM2, human gene and oncogene; MDM2, human protein and isoform; mdm2, mouse gene; Mdm2, mouse protein. Vol. 2, 1–8, January 2004 Molecular Cancer Research 1 Research. on September 6, 2017. © 2004 American Association for Cancer mcr.aacrjournals.org Downloaded from prognostic marker in the absence of both better reagents and a more profound appreciation of the biology underlying MDM2 deregulation and its relationship to the p53-MDM2 axis. Mechanisms of MDM2 Overexpression in Human Cancers Upstream of exon 1 of MDM2, the P1 promotor site regulates the constitutive expression of the full-length MDM2 mRNA. Within the first intron of MDM2, the p53-responsive P2 promotor site regulates the damage inducible expression of an alternatively spliced mRNA species. MDM2 protein overexpression generally results from gene amplification and the concomitant appearance of double minutes (hence, the name murine double minute). Although protein overexpression in the absence of gene amplification has also been observed, activating mutations have not. This suggests that either: (a) MDM2 overexpression can be p53 independent in some cell types; (b) MDM2 preferentially binds to and targets for destruction transcriptionally inactive p53; (c) MDM2 overexpression is, in some settings, a ‘‘readout’’ for transcriptionally active p53; or (d) there are pools within a cell of active and inactive MDM2 that do not directly correlate with overall MDM2 expression but which may reflect different isoforms or modified forms of the protein. Likewise, altered rates of transcription, mRNA stability, enhanced translation, and diminished destruction of the protein all will affect intracellular levels of MDM2. The relative importance of these different mechanisms of MDM2 overexpression in the absence of gene amplification is not known, nor is it clear how they impact on normal MDM2 function and the p53-MDM2 autoregulatory feedback loop.