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The Association of p21^(WAF-1/CIP1) with Progression to Androgen-independent Prostate Cancer¹

Departments of Genitourinary Medical Oncology [K. F., L. A. M., C. R. S., C. J. L., N. M. N.], Biostatistics [D. A. J.], Urology [L. L. P.], Molecular Pathology [T. J. M.], and Pathology [L. C. S., N. G. O., P. T.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Department of Pathology Erasmus University, 3000 DR Rotterdam, the Netherlands [J. T.]

The molecular events leading to progression toward androgen-independent prostate cancer (AIPC) are not fully understood. The p21^(WAF-1/CIP1) (p21) gene has been identified as a key factor for the regulation of cell growth. The expression of p21 was examined by immunohistochemical studies in 105 prostate cancer samples: (a) 7 of 30 (23%) androgen-dependent tumors; and (b) 36 of 75 (48%) androgen-independent tumors stained positive for p21 (P < 0.02). No association was found between p21 expression and p53, bcl-2, and the androgen receptor protein expression in bone metastases of patients with AIPC, whereas there was a significant association with a high Ki-67 index (P < 0.05). In 4 of 43 (9%) cases, tumors displayed a p53-negative, bcl-2-negative, and p21-positive phenotype. A xenograft mouse model of prostate cancer using the androgen-responsive MDA PCa 2b prostate cancer cell line was used to study p21 expression after androgen deprivation and at relapse. Androgen deprivation reduced p21 expression to undetectable levels after 14 days. Tumor relapse, defining AIPC, was associated with increased expression of p21 to levels comparable with those found before castration. In this model, p21 expression at relapse was also correlated with a high Ki-67 index. In conclusion, p21 expression is associated with the progression to AIPC. A possible explanation involves a paracrine effect of p21 mediated by the release of mitogenic and antiapoptotic factors. Another explanation involves the regulation of p21 expression by the androgen receptor, which also suggests that p21 may have antiapoptotic function in prostate cancer.

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