Loss of cell cycle regulators p27(Kip1) and cyclin E in transitional cell carcinoma of the bladder correlates with tumor grade and patient survival

The cyclin-dependent kinase inhibitor p27(Kip1) is a powerful molecular det erminant of cell cycle progression. Loss of expression of p27(Kip1) has bee n shown to be predictive of disease progression in several human malignanci es. In this study we investigated the expression of two key cell, cycle reg ulators, p27(Kip1) and cyclin E, in the progression of transitional cell ca rcinoma of the bladder. An immunohistochemical analysis was conducted Fn a series of 50 bladder tumor specimens, including 3 metastatic lymph nodes, a nd 7 normal bladder specimens, using specific antibodies against the two re gulators of the cell cycle, p27(Kip1) and cyclin E. The degree of immunorea ctivity was correlated with the pathological tumor grade, stage, and patien t survival. A uniformly intense immunoreactivity for p27(Kip1) and cyclin E was observed in epithelial cells of normal bladder tissue. Malignant bladd er 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 c ycle proteins with increasing tumor grade and pathological stage. Expressio n of p27(Kip1) was significantly lower in the poorly differentiated tumors (grades III) compared to well and moderately differentiated (grades I and I I) tumors (P = 0.004). Moreover, the expression of cyclin E was lower in gr ade 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 lo w 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 c linical importance, because they support a role for p27(Kip1) and cyclin E as novel predictive markers of the biological potential of bladder tumors t hat will enable identification of those tumors most likely to progress to m uscle invasive disease and of patient survival.