Aromatase and breast cancer.

Estrogens play an important role in breast cancer development. Aromatase (CYP19), a cytochrome P450, is the enzyme that synthesizes estrogens. Aromatase is expressed at a higher level in human breast cancer tissue than in normal breast tissue using enzyme activity measurement, immunocytochemistry, and RT-PCR analysis. Cell culture, animal experiments using aromatase-transfected breast cancer cells, and transgenic mouse studies have demonstrated that in situ produced estrogen plays a more important role than circulating estrogens in breast tumor promotion. In addition, tumor aromatase has been shown to stimulate breast cancer growth in both an autocrine and a paracrine manner. RT-PCR and gene transcriptional studies have revealed that aromatase promoter switches from a glucocorticoid-stimulated promoter, I.4, in normal tissue to cAMP-stimulated promoters, I.3 and II, in cancereous tissue. Suppression of in situ estrogen biosynthesis can be achieved by the prevention of aromatase expression or by the inhibition of aromatase activity in breast tumors. While the control mechanism of aromatase expression in breast cancer tissue is not yet fully understood, aromatase-inhibitor therapy is considered for second-line treatment in patients who fail anti-estrogen therapy. Twenty to thirty percent of the patients who fail anti-estrogen treatment respond to aromatase-inhibitor treatment. Several potent and selective aromatase inhibitors have been developed and used to treat breast cancer. The binding nature of various aromatase inhibitors has been examined by computer modeling, site-directed mutagenesis of aromatase, and inhibition kinetics. The enzyme structure-function studies have led to the development of a computer model of the active site region of human aromatase. The model is used to evaluate the interaction of phytoestrogens such as flavones and isoflavones with aromatase. The study provides a molecular basis as to why isoflavones are significantly poorer inhibitors of aromatase than flavones. The phytoestrogen studies will help to determine which fruits and vegetables (those containing the appropriate phytoestrogens) should be included in the diet of postmenopausal women in order to reduce the incidence for breast cancer by inhibiting estrogen biosynthesis in breast tissue.