Haapala Kyllikki, Kuukasjärvi Tuula, Hyytinen Eija, Rantala Immo, Helin Heikki J, Koivisto Pasi A
Laboratory of Molecular Genetics, Centre for Laboratory Medicine, Tampere University Hospital, 33521 Tampere, Finland.
Hum Pathol. 2007 Mar;38(3):474-8. doi: 10.1016/j.humpath.2006.09.008. Epub 2007 Jan 10.
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.
激素治疗期间前列腺癌进展的机制以及雄激素受体（AR）基因扩增的病理生物学后果尚不清楚。为了进一步研究AR基因扩增与细胞增殖增加相关的假说，我们分析了123例在雄激素剥夺治疗期间出现肿瘤复发的男性患者的石蜡包埋前列腺癌标本。我们使用荧光原位杂交来量化AR基因拷贝数，并使用Ki-67免疫组织化学来确定细胞增殖情况。三分之一的肿瘤显示AR基因扩增。在有AR扩增的肿瘤中，平均细胞增殖率为19.8（标准差，12.3；95%置信区间[CI]，15.4 - 24.1），而在无扩增的肿瘤中为13.0（标准差，15.9；95%CI，9.1 - 16.8）（P = 0.032）。在最佳拟合逻辑回归模型中，只有增殖仍然具有统计学意义（P = 0.040）。当将所有肿瘤的Ki-67标记指数中位数（6.7%）作为截断点时，有AR扩增的肿瘤比无扩增的肿瘤更频繁地出现高增殖（P = 0.010；优势比，3.4；95%CI，1.4 - 8.3）。我们的结果表明，雄激素剥夺治疗期间前列腺癌的进展与AR基因扩增以及三分之一肿瘤中细胞增殖率增加有关。我们认为AR基因扩增是相当一部分复发性前列腺癌增殖率增加的重要分子机制。然而，应致力于开发前列腺癌细胞系，以研究AR基因扩增与各种生物学变量之间的因果关系。
