Aromatase converts androgen to estrogen. Aromatase is expressed at a higher level in breast cancer tissue than in benign tissue. In situ estrogen biosynthesis in tumor tissue has been shown to play both an autocrine and an endocrine role in promoting tumor growth. Suppression of in situ estrogen biosynthesis can be achieved by the prevention of aromatase expression in breast tumors or by the inhibition of aromatase activity. The regulation of aromatase expression is different in tumor tissue and benign tissue. Aromatase expression in breast tumors was shown to be mainly cAMP driven. It is hypothesized that in normal breast stromal cells, aromatase expression is driven by a promoter (1.4) that is regulated by glucocorticoid, and the action of promoters 1.3 and II is suppressed by a silencer negative regulatory element. However, in cancer tissue, cAMP production increases and aromatase promoters are switched to cAMP-dependent promoters, i.e., 1.3 and II. In addition, a TGFbeta-inhibitory element (TIE) is thought to be present near CREaro, and its action may be down-regulated by estrogen, the product of aromatase. Experiments will be performed to test the hypothesis, and information generated from the proposed experiments will be important for developing approaches to down- regulate aromatase expression in breast tumors. Site-directed mutagenesis will be applied to generate structural information at the active site region of aromatase. Pig and goldfish isoforms of aromatase have been expressed in CHO cells, and their catalytic properties were found to be different from those of the human aromatase. These aromatase isoforms are useful tools for determining the structure-function relationship of aromatase. Results obtained from structure-function studies can be used in the design of more effective treatments of breast cancer by aromatase inhibitors. Finally, treatment by the aromatase inhibitor, aminoglutethimide (AG), has been found to increase aromatase expression both in patients and in cell culture experiments. Results from this laboratory suggest that induction may be mediated through a cAMP-dependent mechanism. Incubation of breast cancer cells with the newly approved inhibitor Arimidex, but not Letrozole, also leads to an increased expression of aromatase. The mechanism of AG and Arimidex induction will be investigated. The proposed approach is critical for achieving the long-term goals: (a) to develop a method to down-regulate aromatase expression in breast tissues; (b) to design more effective mechanism-based aromatase inhibitors; and (c) to improve breast cancer treatment strategies using the currently available drugs.
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