Estrogens and mechanisms of prostate cancer progression
Estrogens and mechanisms of prostate cancer progression
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DOI：
10.1196/annals.1386.027
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发表时间：
2006-01-01
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影响因子：
--
通讯作者：
Carruba, Giuseppe
中科院分区：
文献类型：
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作者：
Carruba, Giuseppe
前列腺癌是西方国家的一个主要健康问题，被认为是一种典型的年龄相关的雄激素依赖性肿瘤。然而，关于循环雄激素和前列腺癌之间的关联的数据一直不一致，大多数与雄激素假说不一致。此外，血浆雄激素与雌激素的比例似乎随着年龄的增长而下降，这表明雌激素也可能起作用。我们自己和其他人的研究结果表明，循环类固醇不能被认为是其实际的前列腺内水平的代表。这是类固醇酶（包括17 β-羟基类固醇脱氢酶（17 β-HSD）、Sa-还原酶、3 α/3 β-HSD和芳香酶）的表达和/或活性的结果，其可最终导致具有不同生物活性的类固醇衍生物的差异组织积累。有趣的是，许多编码类固醇酶的基因在本质上是高度多态的，尽管只有少数研究调查了它们与前列腺癌的关系，目前可用的数据是不确定的。局部产生或代谢转化的雌激素可能会不同地影响前列腺癌细胞的增殖活性。在我们的研究中，雌激素可以刺激或减少前列腺癌细胞的生长，也取决于受体的状态。特别是，ER α和ER β表达的不平衡可能对确定雌激素对前列腺癌细胞生长的最终影响至关重要。此外，越来越多的证据表明，雌激素通过一系列雌激素反应元件（ERE）和非ERE调节基因转录，无论是配体依赖性或非依赖性。这是进一步复杂的受体亚型的存在下，不同的辅因子相互作用，和潜在的异源二聚化。基于这些综合证据，提出了一个假设的前列腺癌进展模型。
Prostate cancer is a major health issue in westernized countries, being considered a prototypical age-related, androgen-dependent tumor. However, data on the association between circulating androgens and prostate cancer have been inconsistent and mostly not compatible with the androgen hypothesis. In addition, plasma androgen-to-estrogen ratio appears to decrease with age, suggesting that estrogens may also have a role. Results from our own and others' studies suggest that circulating steroids cannot be considered representative of their actual intraprostatic levels. This is a consequence of the expression and/or activity of steroid enzymes, including 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), Sa-reductase, 3 alpha/3 beta-HSD, and aromatase, which may eventually lead to a differential tissue accumulation of steroid derivatives having distinct biological activities. Interestingly, many of the genes encoding for steroid enzymes are highly polymorphic in nature, although only a few studies have investigated their relation with prostate cancer and the data presently available are inconclusive. Locally produced or metabolically transformed estrogens may differently affect proliferative activity of prostate cancer cells. In our studies, estrogen may either stimulate or decrease prostate cancer cell growth, also depending on the receptor status. In particular, an imbalance of ER alpha and ER beta expression may be critical to determine the ultimate estrogen effects on prostate cancer cell growth. Furthermore, evidence is accumulating that estrogens regulate gene transcription through an array of estrogen-response elements (EREs) and non-EREs, either ligand-dependent or -independent. This is further complicated by the presence of receptor isoforms, distinct cofactor interaction, and potential heterodimerization. Based on this combined evidence, a hypothetical model of prostate cancer progression is presented.