Loss of Cell Cycle Regulators p27Kip1 and Cyclin E in Transitional Cell Carcinoma of the Bladder Correlates with Tumor Grade and Patient Survival

Abstract

The cyclin-dependent kinase inhibitor p27(Kip1) is a powerful molecular determinant of cell cycle progression. Loss of expression of p27(Kip1) has been shown to be predictive of disease progression in several human malignancies. In this study we investigated the expression of two key cell cycle regulators, p27(Kip1) and cyclin E, in the progression of transitional cell carcinoma of the bladder. An immunohistochemical analysis was conducted in a series of 50 bladder tumor specimens, including 3 metastatic lymph nodes, and 7 normal bladder specimens, using specific antibodies against the two regulators of the cell cycle, p27(Kip1) and cyclin E. The degree of immunoreactivity was correlated with the pathological tumor grade, stage, and patient survival. A uniformly intense immunoreactivity for p27(Kip1) and cyclin E was observed in epithelial cells of normal bladder tissue. Malignant bladder tissue demonstrated a heterogeneous pattern of significantly reduced p27(Kip1) and cyclin E immunoreactivity, compared with normal urothelium (P < 0.01). In addition, there was progressive loss of expression of both cell cycle proteins with increasing tumor grade and pathological stage. Expression of p27(Kip1) was significantly lower in the poorly differentiated tumors (grades III) compared to well and moderately differentiated (grades I and II) tumors (P = 0.004). Moreover, the expression of cyclin E was lower in grade III tumors compared to grade I and II lesions, although this difference failed to reach statistical significance. Most significantly, Kaplan-Meier plots of patient survival show increased mortality risk associated with low levels of p27(Kip1) (P = 0.001) and cyclin E (P = 0.002) expression. This is the first evidence that loss of expression of p27(Kip1) and cyclin E in human bladder transitional cell carcinoma cells correlates with advancing histological aggressiveness and poor patient survival. These results have clinical importance, because they support a role for p27(Kip1) and cyclin E as novel predictive markers of the biological potential of bladder tumors that will enable identification of those tumors most likely to progress to muscle invasive disease and of patient survival.

Cooperative effect of cell-cycle regulators expression on bladder cancer development and biologic aggressiveness

“…To our knowledge, only one study has evaluated the association of p27 expression with outcomes of patients treated with radical cystectomy to date. When evaluated in 26 patients treated with radical cystectomy and 23 patients treated with transurethral resection, Del Pizzo et al 24 reported that p27 expression progressively decreased with increasing tumor stage and was associated with increased all cause mortality in univariate analysis.…”

Expression of p27Kip1 Protein in Transitional Cell Carcinoma of the Upper Urinary Tract

“…With regard to the expression of p27 Kip1 protein in TCC of the urinary tract, to our knowledge, only two reports have been published (15,16). Del Pizzo et al (15), using immunohistochemistry to examine 50 cases of TCC of the urinary bladder, reported that the expression of p27 Kip1 protein was significantly lower in the poorly differentiated tumors and was an independent predictor.…”

“…With regard to the expression of p27 Kip1 protein in TCC of the urinary tract, to our knowledge, only two reports have been published (15,16). Del Pizzo et al (15), using immunohistochemistry to examine 50 cases of TCC of the urinary bladder, reported that the expression of p27 Kip1 protein was significantly lower in the poorly differentiated tumors and was an independent predictor. However, Kuczyk et al (16), who used immunohistochemistry to examine 50 cases of muscle-invasive bladder carcinoma, failed to find a relationship between a low expression of p27 Kip1 protein and either disease-free or overall survival, although the expression of p27 Kip1 protein was related to stage and grade.…”

“…p27 Kip1 is present in large amounts in quiescent cells but has been found to be decreased in malignant tumors. Furthermore, a low expression of p27 Kip1 protein has been found to be associated with tumor aggressiveness and an unfavorable prognosis in several cancers, including those of the urinary bladder (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). In transitional cell carcinoma of the upper urinary tract (TCC-UUT), however, the expression of p27 Kip1 protein has not been examined for its clinical significance in predicting survival.…”

Cyclin E deregulation alters the biologic properties of ovarian cancer cells

“…Even in patients with advanced, suboptimally debulked ovarian epithelial cancers, high cyclin E expression has remained an independent poor prognostic factor (Farley et al, 2003). Cyclin E overexpression has similarly been linked to adverse outcomes in patients with gastric (Jang et al, 1999), bladder (Del Pizzo et al, 1999) and non-small-cell lung carcinomas (Fukuse et al, 2000;Mishina et al, 2000;Muller-Tidow et al, 2001). …”