title: Grape seed extract is an aromatase inhibitor and a suppressor of aromatase expression.
abstract: 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.
authors.affiliation: Department of Surgical Research, Beckman Research Institute of the City of Hope, Duarte, California, USA.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Kijima
authors.forename: Sheryl
authors.initials: S
authors.lastname: Phung
authors.forename: Gene
authors.initials: G
authors.lastname: Hur
authors.forename: Sum-Ling
authors.initials: SL
authors.lastname: Kwok
authors.forename: Shiuan
authors.initials: S
authors.lastname: Chen
mesh_terms: D000818:Animals; D001141:Aromatase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010936:Plant Extracts / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012639:Seeds; D027843:Vitis; D023041:Xenograft Model Antitumor Assays
chemical_list: D047072:Aromatase Inhibitors; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D010936:Plant Extracts; D001141:Aromatase