EXPRESSION OF BCL-2 AND BCL-X IN BLADDER CANCER

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Abstract
TP53 and RB1 gene mutations in bladder transitional cell carcinoma (TCC) are correlated with grade, stage, recurrence, and survival and may correlate with tumor cell apoptotic potential. Overexpression of the bcl-2 and bcl-X anti-apoptotic genes has been correlated with poor prognosis and chemotherapy resistance in other systems. Similar studies have not been performed in TCC. We thus sought to determine expression of bcl-2 and bcl-X in TCC and correlate these with stage, survival and abnormal pRb or p53 expression. Forty-two TCC samples (19 Ta and 23 locally advanced tumors) and normal urothelial controls were examined. Immunohistochemistry for p53, pRb, bcl-2 and bcl-X was performed on an automated system using indirect streptavidin biotin/horseradish peroxidase staining. Western immunoblot analysis was performed on bladder cancer cell lines to further characterize bcl-X expression. Recurrence-free and disease-specific survival were retrospectively determined. Kaplan-Meier survival curves were compared using the log rank test, and correlation of abnormal staining with stage and p53 or pRb status was determined using Fisher's exact test. Bcl-2 was expressed in less than 1% of normal urothelial cells, but moderate expression of bcl-x was found in all normal urothelial samples. Only 7.0% of TCC samples (1/19 Ta and 2/23 locally advanced tumors) demonstrated bcl-2 overexpression. Bcl-X overexpression was observed in 45.2% of TCC (8/19 Ta and 11/23 locally advanced tumors). Western blot analysis also revealed that both the long (29 kDa) anti-apoptotic form and short (19 kDa) pro-apoptotic form were overexpressed in bladder cancer cell lines and normal human urothelial cells. Bcl-X overexpression was weakly correlated with normal p53 expression (p = 0.06). There were no correlations of bcl-2 and bcl-X overexpression with abnormal p53, pRb, or tumor stage. There were no differences in recurrence-free or overall survival in patients with abnormal bcl-X staining. Bcl-2 overexpression is rare in TCC. Bcl-X overexpression is common, likely reflecting its expression pattern in normal urothelium, but is not correlated with stage or abnormal p53 or pRb staining. Within the power limitations of this small study, bcl-X overexpression is not correlated with recurrence or survival.