Regulation of aromatase expression in human tissues.

Extraglandular conversion of C19 steroids to estrogens takes place primarily in the stromal cell compartments of adipose tissue and is catalyzed by aromatase cytochrome P450 (P450arom, the product of the CYP19 gene). CYP19 gene expression and aromatase activity in breast adipose stromal cells in culture are subject to complex hormonal regulation, which was recently found to be mediated in part by alternative use of tissue-specific promoters of the CYP19 gene. It has been proposed that increased local aromatase activity in breast adipose tissue may influence the growth of breast carcinomas. Using competitive RT-PCR, we quantified P450arom transcripts in breast adipose tissue from mastectomy specimens. In 10 out of 15 patients, the highest transcript levels were found in the quadrant where the tumor was located. We also found the highest proportions of adipose stromal cells vs. adipocytes in these quadrants. These findings suggest that regional differences in the relative proportions of the histologic components give rise to local elevated concentrations of estrogens. Although the initiating events are not known, once a neoplastic change has occurred, tumor growth may be promoted by these locally increased estrogen levels. We are currently investigating alternative promoter use for CYP19 gene transcription to explain this association. Our results underscore the importance of aromatase inhibitors as effective agents in treatment of hormone-responsive breast cancer, since aromatase inhibitors reduce local aromatase activity as well as blood estradiol levels.