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(American Journal of Pathology. 1999;155:1129-1136.)
© 1999 American Society for Investigative Pathology

Regular Articles

Loss of Cell Cycle Regulators p27^Kip1 and Cyclin E in Transitional Cell Carcinoma of the Bladder Correlates with Tumor Grade and Patient Survival

Joseph J. Del Pizzo^*, Andrew Borkowski, Stephen C. Jacobs^* and Natasha Kyprianou^*

From the Division of Urology^*
and the Departments of Pathology
and Biochemistry and Molecular Biology,
University of Maryland School of Medicine, Baltimore, Maryland

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.

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