Kijima Ikuko, Phung Sheryl, Hur Gene, Kwok Sum-Ling, Chen Shiuan
Department of Surgical Research, Beckman Research Institute of the City of Hope, Duarte, California, USA.
Cancer Res. 2006 Jun 1;66(11):5960-7. doi: 10.1158/0008-5472.CAN-06-0053.
Aromatase is the enzyme that converts androgen to estrogen. It is expressed at higher levels in breast cancer tissues than normal breast tissues. Grape seed extract (GSE) contains high levels of procyanidin dimers that have been shown in our laboratory to be potent inhibitors of aromatase. In this study, GSE was found to inhibit aromatase activity in a dose-dependent manner and reduce androgen-dependent tumor growth in an aromatase-transfected MCF-7 (MCF-7aro) breast cancer xenograft model, agreeing with our previous findings. We have also examined the effect of GSE on aromatase expression. Reverse transcription-PCR experiments showed that treatment with 60 mug/mL of GSE suppressed the levels of exon I.3-, exon PII-, and exon I.6-containing aromatase mRNAs in MCF-7 and SK-BR-3 cells. The levels of exon I.1-containing mRNA, however, did not change with GSE treatment. Transient transfection experiments with luciferase-aromatase promoter I.3/II or I.4 reporter vectors showed the suppression of the promoter activity in a dose-dependent manner. The GSE treatment also led to the down-regulation of two transcription factors, cyclic AMP-responsive element binding protein-1 (CREB-1) and glucocorticoid receptor (GR). CREB-1 and GR are known to up-regulate aromatase gene expression through promoters I.3/II and I.4, respectively. We believe that these results are exciting in that they show GSE to be potentially useful in the prevention/treatment of hormone-dependent breast cancer through the inhibition of aromatase activity as well as its expression.
芳香化酶是一种将雄激素转化为雌激素的酶。它在乳腺癌组织中的表达水平高于正常乳腺组织。葡萄籽提取物（GSE）含有高水平的原花青素二聚体，我们实验室已证明其为芳香化酶的有效抑制剂。在本研究中，发现GSE以剂量依赖性方式抑制芳香化酶活性，并在芳香化酶转染的MCF-7（MCF-7aro）乳腺癌异种移植模型中减少雄激素依赖性肿瘤生长，这与我们之前的研究结果一致。我们还研究了GSE对芳香化酶表达的影响。逆转录-聚合酶链反应实验表明，用60μg/mL的GSE处理可抑制MCF-7和SK-BR-3细胞中含外显子I.3、外显子PII和外显子I.6的芳香化酶mRNA水平。然而，含外显子I.1的mRNA水平在GSE处理后未发生变化。用荧光素酶-芳香化酶启动子I.3/II或I.4报告载体进行的瞬时转染实验表明，启动子活性以剂量依赖性方式受到抑制。GSE处理还导致两种转录因子，即环磷酸腺苷反应元件结合蛋白-1（CREB-1）和糖皮质激素受体（GR）的下调。已知CREB-1和GR分别通过启动子I.3/II和I.4上调芳香化酶基因表达。我们认为这些结果令人兴奋，因为它们表明GSE通过抑制芳香化酶活性及其表达，在预防/治疗激素依赖性乳腺癌方面可能具有潜在用途。
