Coleman Ilsa M, Kiefer Jeffrey A, Brown Lisha G, Pitts Tiffany E, Nelson Peter S, Brubaker Kristen D, Vessella Robert L, Corey Eva
Fred Hutchinson Cancer Research Center, Seattle, Seattle, WA, USA.
Neoplasia. 2006 Oct;8(10):862-78. doi: 10.1593/neo.06328.
The clinical utility of estrogens for treating prostate cancer (CaP) was established in the 1940s by Huggins. The classic model of the anti-CaP activity of estrogens postulates an indirect mechanism involving the suppression of androgen production. However, clinical and preclinical studies have shown that estrogens exert growth-inhibitory effects on CaP under low-androgen conditions, suggesting additional modes whereby estrogens affect CaP cells and/or the microenvironment. Here we have investigated the activity of 17beta estradiol (E2) against androgen-independent CaP and identified molecular alterations in tumors exposed to E2. E2 treatment inhibited the growth of all four androgen-independent CaP xenografts studied (LuCaP 35V, LuCaP 23.1AI, LuCaP 49, and LuCaP 58) in castrated male mice. The molecular basis of growth suppression was studied by cDNA microarray analysis, which indicated that multiple pathways are altered by E2 treatment. Of particular interest are changes in transcripts encoding proteins that mediate immune responses and regulate androgen receptor signaling. In conclusion, our data show that estrogens have powerful inhibitory effects on CaP in vivo in androgen-depleted environments and suggest novel mechanisms of estrogen-mediated antitumor activity. These results indicate that incorporating estrogens into CaP treatment protocols could enhance therapeutic efficacy even in cases of advanced disease.
20世纪40年代，哈金斯证实了雌激素在治疗前列腺癌（CaP）方面的临床效用。雌激素抗CaP活性的经典模型假定其作用机制是间接的，涉及抑制雄激素的产生。然而，临床和临床前研究表明，在低雄激素条件下，雌激素对CaP具有生长抑制作用，这表明雌激素影响CaP细胞和/或微环境还有其他方式。在此，我们研究了17β-雌二醇（E2）对雄激素非依赖性CaP的活性，并确定了暴露于E2的肿瘤中的分子改变。E2治疗抑制了去势雄性小鼠体内所研究的所有四种雄激素非依赖性CaP异种移植瘤（LuCaP 35V、LuCaP 23.1AI、LuCaP 49和LuCaP 58）的生长。通过cDNA微阵列分析研究了生长抑制的分子基础，结果表明E2治疗改变了多条信号通路。特别值得关注的是，编码介导免疫反应和调节雄激素受体信号蛋白的转录本发生了变化。总之，我们的数据表明，在雄激素缺乏的环境中，雌激素在体内对CaP具有强大的抑制作用，并提示了雌激素介导的抗肿瘤活性的新机制。这些结果表明，将雌激素纳入CaP治疗方案即使在晚期疾病中也能提高治疗效果。
