Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, College of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA.
Endocr Relat Cancer. 2010 Jun 25;17(3):675-89. doi: 10.1677/ERC-09-0294. Print 2010 Sep.
Estrogens play a pivotal role in the development and progression of prostate cancer (PCa). Their actions are mediated by estrogen receptors (ERs), particularly ERbeta in the prostate epithelium. With the discovery of ERbeta isoforms, data from previous studies that focused principally on the wild-type ERbeta (ERbeta1) may not be adequate in explaining the still controversial role of ERbeta(s) in prostate carcinogenesis. In this study, using newly generated isoform-specific antibodies, immunohistochemistry (IHC) was performed on a tumor microarray comprised of 144 specimens. IHC results were correlated with pathological and clinical follow-up data to delineate the distinct roles of ERbeta1, ERbeta2, and ERbeta5 in PCa. ERbeta2 was commonly found in the cytoplasm and was the most abundant isoform followed by ERbeta1 localized predominantly in the nucleus, and ERbeta5 was primarily located in the cytoplasm. Logistic regression analyses demonstrated that nuclear ERbeta2 (nERbeta2) is an independent prognostic marker for prostate specific antigen (PSA) failure and postoperative metastasis (POM). In a Kaplan-Meier analysis, the combined expression of both nERbeta2 and cytoplasmic ERbeta5 identified a group of patients with the shortest POM-free survival. Cox proportional hazard models revealed that nERbeta2 predicted shorter time to POM. In concordance with IHC data, stable, ectopic expression of ERbeta2 or ERbeta5 enhanced PCa cell invasiveness but only PCa cells expressing ERbeta5 exhibited augmented cell migration. This is the first study to uncover a metastasis-promoting role of ERbeta2 and ERbeta5 in PCa, and show that the two isoforms, singularly and conjointly, have prognostic values for PCa progression. These findings may aid future clinical management of PCa.
雌激素在前列腺癌（PCa）的发展和进展中起着关键作用。它们的作用是通过雌激素受体（ERs）介导的，特别是在前列腺上皮细胞中的 ERbeta。随着 ERbeta 同工型的发现，以前主要集中在野生型 ERbeta（ERbeta1）上的研究数据可能不足以解释 ERbeta（s）在前列腺癌发生中的仍然存在争议的作用。在这项研究中，使用新生成的同工型特异性抗体，对由 144 个标本组成的肿瘤微阵列进行了免疫组织化学（IHC）。将 IHC 结果与病理和临床随访数据相关联，以描绘 ERbeta1、ERbeta2 和 ERbeta5 在 PCa 中的不同作用。ERbeta2 通常在细胞质中发现，是最丰富的同工型，其次是主要定位于细胞核中的 ERbeta1，而 ERbeta5 主要位于细胞质中。逻辑回归分析表明，核 ERbeta2（nERbeta2）是前列腺特异性抗原（PSA）失败和术后转移（POM）的独立预后标志物。在 Kaplan-Meier 分析中，nERbeta2 和细胞质 ERbeta5 的联合表达确定了一组具有最短 POM 无生存时间的患者。Cox 比例风险模型显示，nERbeta2 预测 POM 时间较短。与 IHC 数据一致，ERbeta2 或 ERbeta5 的稳定异位表达增强了 PCa 细胞的侵袭性，但只有表达 ERbeta5 的 PCa 细胞表现出增强的细胞迁移。这是第一项揭示 ERbeta2 和 ERbeta5 在 PCa 中促进转移作用的研究，并表明这两个同工型单独和共同对 PCa 进展具有预后价值。这些发现可能有助于未来 PCa 的临床管理。
