P53 Isoform Expression in Serous Ovarian Cancer
P53 Isoform Expression in Serous Ovarian Cancer
Identification of biomarkers that could inform a therapeutic strategy is an essential step in developing targeted personalized therapy. In the design of clinical trials that study therapeutic approaches targeting p53, the p53 status (mutation vs wild-type) is frequently used for triaging or classifying patients. In a recent review, the National Cancer Institute (NCI) clinical trials database listed 151 trials that exploit the p53 pathway. However, as this paper by Hofstetter et al. demonstrates, the p53 network is complex and mutation status is probably not a sufficient determinant of p53 pathway activity. In this respect, the studies by Hofstetter and colleagues are important because detecting the presence of p53 isoforms may be useful to more accurately stratify patients for clinical trials. These results also have therapeutic implications. Therapeutic approaches could be modified to take into account these new findings. For example, gene therapy approaches to restore wild-type p53 function could deliver a p53 isoform (instead of the wild-type p53 gene) to patients whose tumors harbor an inactivated p53. Activating wild-type p53 and/or inactivating mutant p53 by modulating these p53 isoform regulators are other potential approaches. It is important that a better understanding is gained of interactions within what is clearly a complex p53 network.
These results also have mechanistic implications. Loss of p53 is a common event during tumorigenesis, suggesting that inactivation of this tumor suppressor is a key event during tumorigenesis. However, regulation of the p53 pathway is complex and mutations in the p53 gene result in the expression of a mutant protein that has oncogenic activity. Hence, the notion that p53 mutations inactivate the p53 pathway is an oversimplification. More recently, the discovery of two other p53 family members, p63 and p73, and of at least a dozen truncated p53 isoforms that can interact with and modify the activity of the full-length protein, suggests that these isoforms play a key role in regulation of p53. Several studies have shown that Δ133p53 proteins are present at elevated levels in the cells of some tumor types, suggesting that they may play a role in tumorigenesis. The results by Hofstetter and colleagues support this notion and suggest that the Δ133p53 and Δ40p53 isoforms may either substitute for the wild-type p53 protein or suppress the actions of mutant p53 and ameliorate the loss of p53 tumor suppressor activity. Hence, these two isoforms may have modest tumor suppressor activity in their own right. Further studies in other tumors and of other isoforms will be necessary to elucidate the full implications of p53 isoforms and their role in a malfunctioning p53 pathway in human tumors.
Future Perspective
Identification of biomarkers that could inform a therapeutic strategy is an essential step in developing targeted personalized therapy. In the design of clinical trials that study therapeutic approaches targeting p53, the p53 status (mutation vs wild-type) is frequently used for triaging or classifying patients. In a recent review, the National Cancer Institute (NCI) clinical trials database listed 151 trials that exploit the p53 pathway. However, as this paper by Hofstetter et al. demonstrates, the p53 network is complex and mutation status is probably not a sufficient determinant of p53 pathway activity. In this respect, the studies by Hofstetter and colleagues are important because detecting the presence of p53 isoforms may be useful to more accurately stratify patients for clinical trials. These results also have therapeutic implications. Therapeutic approaches could be modified to take into account these new findings. For example, gene therapy approaches to restore wild-type p53 function could deliver a p53 isoform (instead of the wild-type p53 gene) to patients whose tumors harbor an inactivated p53. Activating wild-type p53 and/or inactivating mutant p53 by modulating these p53 isoform regulators are other potential approaches. It is important that a better understanding is gained of interactions within what is clearly a complex p53 network.
These results also have mechanistic implications. Loss of p53 is a common event during tumorigenesis, suggesting that inactivation of this tumor suppressor is a key event during tumorigenesis. However, regulation of the p53 pathway is complex and mutations in the p53 gene result in the expression of a mutant protein that has oncogenic activity. Hence, the notion that p53 mutations inactivate the p53 pathway is an oversimplification. More recently, the discovery of two other p53 family members, p63 and p73, and of at least a dozen truncated p53 isoforms that can interact with and modify the activity of the full-length protein, suggests that these isoforms play a key role in regulation of p53. Several studies have shown that Δ133p53 proteins are present at elevated levels in the cells of some tumor types, suggesting that they may play a role in tumorigenesis. The results by Hofstetter and colleagues support this notion and suggest that the Δ133p53 and Δ40p53 isoforms may either substitute for the wild-type p53 protein or suppress the actions of mutant p53 and ameliorate the loss of p53 tumor suppressor activity. Hence, these two isoforms may have modest tumor suppressor activity in their own right. Further studies in other tumors and of other isoforms will be necessary to elucidate the full implications of p53 isoforms and their role in a malfunctioning p53 pathway in human tumors.
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