BERKELEY, CA (UroToday.com) - UroToday – The existence of preclinical data on interconnections between p53, cyclooxygenase-2 (COX-2) and cyclin D1 signaling proteins in prostate cancer (PCa) prompted our interest to investigate their interrelations at the clinical level as well as their potential prognostic value after radical prostatectomy (RP) in hormone-naïve patients with early stage PCa.
Therefore, we performed p53, COX-2 and cyclin D1 immunostaining and recorded clinical data prospectively, particularly focusing on time to biochemical failure (TTBF), which is as an established precursor of progression to metastatic disease. We demonstrated that p53 might be considered a potential prognostic marker, as patients with high protein expression had a statistically significant shorter TTBF. Moreover, elevated p53 expression was also found to be an independent prognostic factor in a multivariate model including known predictors of clinical outcome, such as pathological TNM stage and Gleason score.
The low cutoff value for p53 positivity (5%) used in our study was intended to be representative of the biological significance of p53 protein overexpression which is a result of p53 gene inactivation and a rare event in primary prostatic tumors, arising relatively late during neoplastic progression . Thus, any detection of p53 protein immunoreactivity could be considered indirect evidence of p53 gene mutation. This is in line with previous studies in which p53 expression was considered aberrant, either using a low positive p53 immunostaining threshold (e.g. >1%, >10%) [2-4], or regardless of the percentage of cells stained [5-12]. We suggest that a patient with negative or low p53 staining is likely to have a good prognosis, based on a longer TTBF.
Although we failed to confirm any statistically significant roles for COX-2 or Cyclin D1 expression as predictors of BF, we did find a direct correlation of both proteins with p53, in line with the underlying biology. According to the latter, the absence of functional p53, which is largely indicated by aberrant p53 protein expression, is synonymous with abrogation of p53-mediated COX-2 and cyclin D1 repression [13-15]. We believe that the existence of significant interconnections between these 3 immunohistochemical markers both in vitro, as already known from gross amount of literature, and in vivo as we have demonstrated, might necessitate their simultaneous examination in future studies.
Several limitations of our study should also be considered. It should be acknowledged that the small number of patients included in the present study does not permit to draw unequivocal conclusions. Further, lowest Gleason scores (2, 3, 4) are not represented in the study population and this might also blunt the validity of our results, as well as retrospective review of our prospectively collected data and the relatively short median follow-up of patients. Moreover, the prognostic values of p53, COX-2 and cyclin D1 might have been better established if they had been compared to predicted outcomes of validated nomograms. Finally, our study was not intended to be all-inclusive of current prognostic markers such as pre-operative PSA, surgical margin status, seminal vesicle involvement, tumor marker ploidy and proliferation indexes.
Our study was designed in an effort to offer an integrated approach of the role of the p53, COX-2 and cyclin D1 pathways in the clinical course of PCa patients. Although further prospective evaluation to confirm their interactions is required, the correlation between an aggressive PCa phenotype and concurrent aberrations of p53, COX-2 and cyclin D1 signalling seems to play a role in the clinical setting.
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Panagiotis J. Vlachostergios. MD., Et Al. as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.