Androgen receptor expression in relation to apoptosis and the expression of cell cycle related proteins in prostate cancer (original) (raw)
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Significance of p53 and ki-67 expression in prostate cancer
Urology Annals, 2015
Prostate cancer is the second most frequently diagnosed cancer and the fifth leading cause of cancer death in males. [1] Incidence increases from 20% in men in their fifties to approximately 70% in men between the age of 70 and 80 years. [2] Prostate cancer is not only significant for its lethality but also for the extremely high morbidity associated with it. Nowadays, more patients are diagnosed at earlier stages, due to increased availability of prostatic-specific antigen (PSA) measurement and other diagnostic methods. With delay in diagnosis of the low-grade tumor, the quality or length of patient's life is not significantly changed, but a high-grade tumor in a young person might spread quickly and lead to the patient's death within 2 years. The absence of prognostic information has also led to significant "overtreatment" of patients who would otherwise require only conservative management. Background: Prostate cancer is a major health problem throughout the developed world. Tumor grade is one of the most important prognostic factors of prostate cancer. At present, adequate prognostic markers for prostate cancer progression are still lacking, in spite of intensive investigation. Accordingly, we studied the role of immunohistochemical (IHC) expression of p53 and Ki-67 as a prognostic factor in carcinoma prostate and correlated their expression with Gleason's grade. Materials and Methods: In this prospective study, a total of 60 cases including 50 cases of prostate carcinoma and 10 of benign prostatic hyperplasia (BPH) were taken. Tumor grade was determined according to Gleason's grading system. p53 and Ki-67 expressions were determined by IHC staining. The obtained results were analyzed and evaluated using Spearman's statistical test (SPSS version 20). Results: In BPH, p53 was expressed in only 2 of 10 (20%) cases while in carcinoma it was expressed in 38 of 50 (76%) cases. Ki-67 was expressed in only 1 of 10 (10%) BPH cases while in carcinoma it was expressed in 32 of 50 (64%) cases. In present study, 1 of 4 (25%) well differentiated, 23 of 31 (74.19%) moderately differentiated and 14 of 15 (93.33%) poorly differentiated tumors revealed p53 immunopositivity and a statistically significant correlation was observed between p53 expression and increased Gleason's grade (P = 0.038). All 4 (100%) cases of well-differentiated carcinoma were negative for Ki-67 expression. Nineteen of 31 (61.29%) moderately differentiated and 13 of 15 (86.66%) poorly differentiated tumors were positive for Ki-67 and a statistically significant correlation was observed between Ki-67 positivity and increased Gleason's grade (P = 0.002). Conclusions: Both p53 and Ki-67 were significantly up-regulated in malignant lesions as compared to benign lesions and a strong relationship with the Gleason's grading was noticed, therefore, we propose that these markers can be applied along with other prostate cancer prognostic factors.
Gene Expression of P 53 and Bcl-2 as Markers of Prostate Cancer Progression
2017
Introduction: Apoptotic genes regulate apoptosis by the action of their proand antiapoptotic products. Among the most important proteins are p53 and Bcl-2 proteins. The rate of tumor growth is dependent on the balance between proliferation and apoptosis at all stages of carcinogenesis. The differential expression of these apoptotic genes was analyzed in relation to clinicopathological criteria as Gleason Score in man with Prostate Cancer. Every prostate cancer patient who underwent histopathology examination which fulfill the criteria were included in the study. Samples then rearrange into low Gleason Score (2-6) and high Gleason Score (7-10). All samples then underwent gene expression assay for p53 and bcl-2 to be analyzed for each’s relationship with each group. The aim of this study was to evaluate tumor proliferation and the expression of the proto-oncogene Bcl-2 and tumor suppressor gene p53 in patients undergoing transurethral prostatectomy for prostate cancer, and to define t...
Can p53, Ki-67 and bcl-2 predict biochemical failure after radical prostatectomy?
Indian Journal of Urology, 2010
Background and Objective: Background and Objective: To analyze p53, Ki-67 and bcl-2 expressions immunohistochemically and their predictive role To analyze p53, Ki-67 and bcl-2 expressions immunohistochemically and their predictive role in biochemical recurrence after radical prostatectomy. in biochemical recurrence after radical prostatectomy. Materials and Methods: Materials and Methods: Seventy one patients who had undergone radical prostatectomy between 1992 and 2001 were Seventy one patients who had undergone radical prostatectomy between 1992 and 2001 were randomly selected. Tissue microarrays were constructed from their radical prostatectomy specimens. They contained four randomly selected. Tissue microarrays were constructed from their radical prostatectomy specimens. They contained four cores from neoplastic and additional four cores from corresponding non-neoplastic regions. Gleason score ranged from cores from neoplastic and additional four cores from corresponding non-neoplastic regions. Gleason score ranged from 6-9, and pathological stage ranged from T2N0Mx to T3BN1. Staining for bcl-2 was scored visually taking percent negative, 6-9, and pathological stage ranged from T2N0Mx to T3BN1. Staining for bcl-2 was scored visually taking percent negative, weak, moderate and strong positivity into consideration. Strong immunoreactivity was considered positive for p53. Ki-67 weak, moderate and strong positivity into consideration. Strong immunoreactivity was considered positive for p53. Ki-67 index was measured as the percentage of positive nuclei among tumor cells. Statistical analysis was performed to explore index was measured as the percentage of positive nuclei among tumor cells. Statistical analysis was performed to explore correlations between staining patterns and clinicopathological prognostic parameters. correlations between staining patterns and clinicopathological prognostic parameters. Results: Results: The follow-up period extended from 13 to 112 months with a mean 60 (48 ± 23, 2) months. Of all, 38.02% had The follow-up period extended from 13 to 112 months with a mean 60 (48 ± 23, 2) months. Of all, 38.02% had no evidence of disease, 52.1% were alive with disease and 9.8% were died during follow-up. The expression of p53, Ki-no evidence of disease, 52.1% were alive with disease and 9.8% were died during follow-up. The expression of p53, Ki-67 and bcl-2 in tumors were 39%, 76% and 5% respectively. While the secretory layer showed negative or weak bcl-2 67 and bcl-2 in tumors were 39%, 76% and 5% respectively. While the secretory layer showed negative or weak bcl-2 staining in most cases, expression in basal cells was often stronger. Statistical analysis revealed differences in staining staining in most cases, expression in basal cells was often stronger. Statistical analysis revealed differences in staining between normal and carcinoma for all three markers. There was no correlation between staining patterns and time to between normal and carcinoma for all three markers. There was no correlation between staining patterns and time to biochemical relapse. On the other hand, cases with higher Gleason sum showed the tendency for over expression of p53, biochemical relapse. On the other hand, cases with higher Gleason sum showed the tendency for over expression of p53, Ki-67 and bcl-2 although the differences were not statistically different. Multivariate analysis revealed CMS group and Ki-67 and bcl-2 although the differences were not statistically different. Multivariate analysis revealed CMS group and seminal vesicle invasion as the independent predictors of PSA failure (log rank seminal vesicle invasion as the independent predictors of PSA failure (log rank P = 0.0039 and = 0.0039 and P = 0.001, respectively). = 0.001, respectively). Conclusion: Conclusion: The proteins bcl-2, p53 and Ki-67 were expressed at a different rate in normal and neoplastic prostate tissue. The proteins bcl-2, p53 and Ki-67 were expressed at a different rate in normal and neoplastic prostate tissue. Bcl-2 was mainly expressed by basal cells in normal glands. p53 and Ki-67 expression were increased in most prostate Bcl-2 was mainly expressed by basal cells in normal glands. p53 and Ki-67 expression were increased in most prostate carcinomas. However, overall expression levels did not correlate with biochemical recurrence in this study. carcinomas. However, overall expression levels did not correlate with biochemical recurrence in this study.
Mechanisms of prostate cancer cell survival after inhibition of AR expression
Journal of Cellular Biochemistry, 2009
Recent reports have shown that the AR is the key determinant of the molecular changes required for driving prostate cancer cells from an androgen-dependent to an androgen-independent or androgen depletion-independent (ADI) state. Several recent publications suggest that down-regulation of AR expression should therefore be considered the principal strategy for the treatment of ADI prostate cancer. However, no valid data is available about how androgen-dependent prostate cancer cells respond to apoptosis-inducing drugs after knocking down AR expression and whether prostate cancer cells escape apoptosis after inhibition of AR expression. This review will focus on mechanisms of prostate cancer cell survival after inhibition of AR activity mediated either by androgen depletion or by targeting the expression of AR by siRNA. We have shown that knocking down AR expression by siRNA induced PI3K-independent activation of Akt, which was mediated by calcium/calmodulin-dependent kinase II (CaMKII). We also showed that the expression of CaMKII genes is under AR control: active AR in the presence of androgens inhibits CaMKII gene expression whereas inhibition of AR activity results in an elevated level of kinase activity and in enhanced expression of CaMKII genes. This in turn activates the anti-apoptotic PI3K/Akt pathways. CaMKII also express anti-apoptotic activity that is independent from the Akt pathway. This may therefore be an important mechanism by which prostate cancer cells escape apoptosis after androgen depletion or knocking down AR expression. In addition, we have found that there is another way to escape cell death after AR inhibition: DNA damaging agents cannot fully activate p53 in the absence of AR and as a result p53 down stream targets, for example, microRNA-34, cannot be activated and induce apoptosis. This implies that there may be a need for re-evaluation of the therapeutic approaches to human prostate cancer. J. Cell. Biochem. 106: 363–371, 2009. © 2008 Wiley-Liss, Inc.
Prognostic Value of Amacr and Ki-67 in Progression of Prostate Cancer
Prostate cancer is the second most frequently diagnosed cancer and the fifth leading cause of cancer death in male Incidence increases from 20% in men in their fifties to approximately 70% in men between the age of 70 and 80 years. Prostate cancer is not only significant for its lethality but also for the extremely high morbidity associated with it. Immunohistochemistry has proven to be an extremely important tool in the monitoring of the progression prostatic carcinoma as the immunohistochemical markers are known to be specific in nature. BPH and PCa was calculated and presented as; 10% in normal, 15% BPH and 100% PCa in AMACR. The mean percentage immunoreactivity for LGPIN and HGPIN was also calculated as 60% in and 50% in LGPIN and 75% in HGPIN when stained with AMACR. The expression of and AMACR in Normal, BPH and Pca tissue has therefore confirmed the ability of this markers effectiveness in predicting the progression of normal prostatic tissue, to prostatic carcinoma.
Experimental and Therapeutic Medicine, 2010
Apoptosis is a form of programmed cell death necessary for the regulation of the size of organs in adult life. Disruption of apoptotic pathways has been suggested as an important regulatory mechanism in prostatic tumours. The aim of this study was to examine the expression of apoptosisregulating genes bcl-2 and p53 using immunohistochemistry, and the Gleason score in core needle biopsy specimens of prostate adenocarcinoma. We studied bcl-2 and p53 expression in 30 cases of low-, 30 cases of intermediate-and 20 cases of high-grade prostate adenocarcinoma. Overexpression of bcl-2 and p53 were noted in 54 and 61 of 80 patients (67.5 and 76.25%), respectively. The statistical analysis of the present data suggested that there is significant relation between p53 and bcl-2 expression, and Gleason score in prostate cancer. Thus, immunohistochemistry is a useful investigative parameter in assessing apoptosis to analyse the prognosis of prostatic tumours.
European Urology, 2005
Purposes: To elucidate the prognostic value of the immunohistochemical (IHC) expression of Bcl-2, Bax, Cox-2 and Ki-67 antigen in biopsy cores (C) and surgical specimens (SP) of prostate cancer (PC) and to determine the C to SP reproducibility. Material and methods: The IHC study was carried out in 91 patients operated by means of radical prostatectomy (RP) with available formalin-fixed paraffin-embedded material from both C and SP. Results: The IHC expression of Bcl-2 in C and SP was very low (5%). Bax was expressed in almost all the patients and did not show any prognostic value. We observed a good reproducibility between C and SP for all molecules except with Bax. In prostate C, Ki-67 and Cox-2 were considered positive in 42.9% and 67% of the patients respectively, and were related to disease-free survival in the univariate analysis. The expression of these two markers in SP was observed in 51.6% and 79.1% of the patients and the expression of Ki-67 in SP maintained its independence as prognostic factor in the multivariate analysis related to disease-free survival. Conclusions: The IHC expression of Ki-67 and Cox-2 proteins in our study do offer valuable prognostic information, mostly the first one. Thus, we think these markers might be studied in larger series of patients for its further validation as prognostic factors in prostate biopsies. #
Clinical Cancer Research
The quest for prognostic molecular markers in prostatic carcinoma is still in progress. Many proteins have already been screened by immunohistochemistry with the aim to find the most reliable indicator of progressive disease. In this study, we evaluated the expression of pRb2/p130, p107, p27(kip1), p53, mdm-2, and Ki-67 (MIB-1) by immunohistochemistry in 24 prostate carcinomas compared with the paired expression of normal prostates. Expression of the different proteins in normal and pathological specimens was evaluated by the Wilcoxon test. A matrix of correlation (Spearman coefficient) was used to evaluate the possible association in expression among the different proteins. Logistic regression analysis was used to test the multivariable prognostic value of the levels of protein expression for the probability of disease development. p53 and Ki-67 (MIB-1) showed a higher expression in cancer than in normal tissue (P = 0.006 and <0.001, respectively). pRb2/p130, p107, and p27(kip1)...
p53 Status and Prognosis of Locally Advanced Prostatic Adenocarcinoma: a Study Based on RTOG 8610
Background: The p53 tumor suppressor gene (also known as TP53) is one of the most frequently mutated genes in human cancer. Several studies have shown that p53 mutations are infrequent in prostate cancer and are associated with advanced disease. Purpose: We assessed the prognostic value of identifying abnormal p53 protein expression in the tumors of patients with locally advanced prostate cancer who were treated with either external-beam radiation therapy alone or total androgen blockade before and during the radiation therapy. Methods: The study population consisted of a subset of patients entered in Radiation Therapy Oncology Group protocol 8610 (''a phase III trial of Zoladex and flutamide used as cytoreductive agents in locally advanced carcinoma of the prostate treated with definitive radiotherapy''). Immunohistochemical detection of abnormal p53 protein in pretreatment specimens (i.e., needle biopsies or transurethral resections) was achieved by use of the monoclonal anti-p53 antibody DO7; specimens in which 20% or more of the tumor cell nuclei showed positive immunoreactivity were considered to have abnormal p53 protein expression. Associations between p53 protein expression status and the time to local progression, the incidence of distant metastases, progression-free survival, and overall survival were evaluated in univariate (logrank test) and multivariate (Cox proportional hazards model) analyses. Reported P values are two-sided. Results: One hundred twenty-nine (27%) of the 471 patients entered in the trial had sufficient tumor material for analysis. Abnormal p53 protein expression was detected in the tumors of 23 (18%) of these 129 patients. Statistically significant associations were found between the presence of abnormal p53 protein expression and increased incidence of distant metastases (P = .04), decreased progression-free survival (P = .03), and decreased overall survival (P = .02); no association was found between abnormal p53 protein expression and the time to local progression (P = .58). These results were independent of the Gleason score and clinical stage. A significant treatment interaction was detected with respect to the development of distant metastases: Among patients receiving both radiation therapy and hormone therapy, those with tumors exhibiting abnormal p53 protein expression experienced a reduced time to the development of distant metastases (P = .001); for patients treated with radiation therapy alone, the time to distant metastases was unrelated to p53 protein expression status (P = .91). Conclusions: Determination of p53 protein expression status yields signifi-cant, independent prognostic information concerning the development of distant metastases, progression-free survival, and overall survival for patients with locally advanced prostate cancer who are treated primarily with radiation therapy. Implications: The interaction of radiation therapy plus hormone therapy and abnormal p53 protein expression may provide a clinical link to experimental evidence that radiation therapy and/or hormone therapy act, at least in part, by the induction of apoptosis (a cell death program) and suggests that this mechanism may be blocked in patients whose tumors have p53 mutations. [J Natl Cancer Inst 1997; 89:158-65]
Apoptosis in prostate cancer: Bax correlation with stage
International Journal of Urology, 2005
Background : Dysregulation of apoptosis may contribute to the process of prostate tumorigenesis by reducing the rate of cell death. Bcl-2 and bax are important molecules involved in the regulation of apoptosis. The aim of the present study is to examine apoptosis and related regulatory molecular markers in a group of Iranian patients with prostate cancer. Methods : Paraffin-embedded tissues from 50 patients of prostate carcinoma were examined for the expression of bcl-2 antiapoptotic and bax proapoptotic markers and also proliferation marker, Ki-67, by immunohistochemistry. Detection of apoptotic cells was performed using TUNEL method. Correlation between apoptotic index, proliferation index and bcl-2 and bax expression with stage, pathological grade and Gleason score was determined. Results : Apoptosis was detected in 12% of prostate cancers. No correlation was observed between apoptosis and differentiation status of carcinoma. Bcl-2 expression was detected in 21 of samples. A significant correlation between bcl-2 expression and Ki-67 staining index (r = 0.349, P = 0.012) was observed. High bax protein expression was shown in our study. We found a significant correlation between bax expression and stage of carcinoma (r = 0.388, P = 0.031), but not with the apoptosis index, suggesting the presence of a non-functional bax protein or the role of other proapoptotic molecules. Conclusion : The patients in the present study showed a different pattern of apoptosis positivity compared to other reports. Bax expression may be a useful marker for prognosis of prostate cancer.