Mechanisms of
prostate cancer progression during hormonal
therapy and the pathobiologic consequences of
androgen receptor (AR) gene amplification are inadequately known. To further investigate the hypothesis that AR gene amplification is associated with increased cell proliferation, we analyzed 123
paraffin-embedded
prostate cancer specimens from men who experienced
tumor relapse during
androgen withdrawal
therapy. We used fluorescence in situ hybridization to quantify AR gene copy number and Ki-67 immunohistochemistry to determine cell proliferation. One third of the
tumors showed AR gene amplification. Among
tumors with AR amplification, the mean cell proliferation rate was 19.8 (SD, 12.3; 95% confidence interval [CI], 15.4-24.1), whereas it was 13.0 (SD, 15.9; 95% CI, 9.1-16.8) in
tumors without amplification (P = .032). In the best fitting logistic regression model, only proliferation remained significant (P = .040). When the median Ki-67 labeling index (6.7%) of all
tumors was used as a cutoff point, the
tumors with AR amplification were more frequently highly proliferating than
tumors with no amplification (P = .010; odds ratio, 3.4; 95% CI, 1.4-8.3). Our results imply that progression of
prostate cancer during
androgen withdrawal
therapy is associated with AR gene amplification and increased cell proliferation rate in one third of
tumors. We suggest that AR gene amplification is an important molecular mechanism underlying the increase in proliferation rate of a substantial fraction of recurrent prostate
carcinomas. However, efforts should be targeted to develop
prostate cancer cell lines to study causal relationships between AR gene amplification and various biologic variables.