| Breast cancer is one of the most common cancers affecting women. Estrogen plays an important role in breast cancer initiation and development. The majority of breast tumors are initially dependent upon estrogen to support their growth. Most breast cancers occur in the postmenopausal period. However, the intra-tumoral estradiol (E2) is maintained at a high level equivalent to the pre-menopausal status. High intra-tumoral E2 level in postmenopausal women is sustained by the biosynthesis of estrogens in the tumorous tissue.;The aromatase enzyme, CYP19, belongs to a family of P450 enzyme. As a final rate-limiting step in estrogen biosynthesis, it catalyzes the conversion of C 19 steroids to estrogens. The expression of CYP19 is tissue-specific, and is regulated by alternate promoter usage. The use of aromatase inhibitors for breast cancer treatment has become a major therapeutic approach.;The consumption of some phytochemicals protects against breast cancer. Yet the mechanisms are far from clear. In my present study, various phytochemicals, including phytoestrogens, monoterpenes and carotenoids, were evaluated for their effect on aromatase.;A breast cancer cell line stably transfected with the CYP19 gene had been employed for aromatase inhibition. Among the phytochemicals tested, the major dietary flavonoids, such as genistein and daidzein, produced very weak inhibition. On the other hand, the red clover isoflavone biochanin A, the hydroxychalcone butein and the red grape phytoalexin resveratrol were found to be effective aromatase inhibitors. Cell proliferation assay had shown that they could inhibit ER-positive cell proliferation induced by testosterone, and the inhibitory effect was specifically attributed to the reduction of estrogen synthesis. In another breast cancer cell line SK-BR-3, resveratrol, biochanin A and genistein inhibited CYP19 both in enzyme and promoter I.3/II transcriptional levels. The element responsible for the inhibition of aromatase by these phytoestrogens should fall within the region between -556 to -446 by upstream of exon II.;Genistein and Biochanin A, ranged from 0.1 to 10 muM, might act as estrogen agonist and induced aromatase activity and promoter I.1 transactivation in ERalpha-transfected SK-BR-3 cells. (Abstract shortened by UMI.). |
