17β-Hydroxysteroid Dehydrogenase Type 1 Stimulates Breast Cancer by Dihydrotestosterone Inactivation in Addition to Estradiol Production
17β-Hydroxysteroid Dehydrogenase Type 1 Stimulates Breast Cancer by Dihydrotestosterone Inactivation in Addition to Estradiol Production
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DOI：
10.1210/me.2009-0468
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发表时间：
2010-04-01
影响因子：
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通讯作者：
Lin, Sheng-Xiang
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作者：
Aka, Juliette A.;Mazumdar, Mausumi;Lin, Sheng-Xiang
活性雌激素雌二醇（E2）刺激乳腺癌细胞（BCC）的生长，而雄激素双氢睾酮（DHT）已显示出抗增殖作用。由17 β-羟基类固醇脱氢酶1型（17 β-HSD 1）合成的主要产物是E2，尽管我们已经证明纯化的酶也使DHT失活。然而，17 β-HSD 1在性激素调节和BCC增殖中的直接作用尚未完全确定。在这里，我们表明，17 β-HSD 1抑制抑制DHT的catalysts由19%，而敲低的基因表达增加了41%的浓度的DHT在T47 D BCC线。17 β-HSD 1/DHT复合物晶体结构揭示了DHT以正常和反向模式结合，但导致O3还原的后一种模式具有更强的相互作用。使用RNA干扰和17 β-HSD 1的抑制剂，我们证明了17 β-HSD 1的表达与BCC中的DHT水平呈负相关，但与雌酮减少、E2水平和细胞增殖呈正相关。17 β-HSD 1抑制减少了DHT失活，增加了处理8天后DHT在T47 D细胞中的抗增殖作用。因此，17 β-HSD 1通过对雌二醇合成和DHT失活的双重作用上调BCC生长。我们已经进一步证明，17 β-HSD 1可以增强E2诱导的内源性雌激素反应基因pS2的表达，提供了关于17 β-HSD 1调节雌激素反应性的重要信息，这也可能有助于BCC生长。这些结果强烈支持在乳腺癌治疗中抑制17 β-HSD 1以通过硫酸酯酶途径消除雌激素活化同时避免剥夺DHT的基本原理。（分子内分泌学24：832-845，2010）
The active estrogen estradiol (E2) stimulates breast cancer cell (BCC) growth, whereas the androgen dihydrotestosterone (DHT) has shown an antiproliferative effect. The principal product synthesized by the 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) is E2, although we have demonstrated that the purified enzyme also inactivates DHT. However, the direct roles of 17 beta-HSD1 in sex-hormone regulation and BCC proliferation have not been completely established. Here, we show that 17 beta-HSD1 inhibition suppresses DHT catabolism by 19%, whereas knockdown of the gene expression increases the concentration of DHT by 41% in the T47D BCC line. The 17 beta-HSD1/DHT complex crystal structure reveals that DHT binds in both normal and reverse modes, but the latter mode leading to O3 reduction is preferred with stronger interactions. Using RNA interference and an inhibitor of 17 beta-HSD1, we demonstrate that 17 beta-HSD1 expression is negatively correlated to DHT levels in BCC but positively correlated to estrone reduction, E2 levels, and cell proliferation. 17 beta-HSD1 inhibition reduces DHT inactivation, increasing the antiproliferative effect by DHT in T47D cells after 8 d treatment. Thus, 17 beta-HSD1 up-regulates BCC growth by a dual action on estradiol synthesis and DHT inactivation. We have further demonstrated that 17 beta-HSD1 can enhance the E2-induced expression of the endogenous estrogen-responsive gene pS2, providing an important information regarding the modulation of the estrogen responsiveness by 17 beta-HSD1 that may also contribute to BCC growth. These results strongly support the rationale for inhibiting 17 beta-HSD1 in breast cancer therapy to eliminate estrogen activation via the sulfatase pathway while avoiding the deprivation of DHT. (Molecular Endocrinology 24: 832-845, 2010)