Biological Significance of Aromatase Activity in Human Breast Tumors*

Abstract

Human breast carcinomas contain aromatase, the enzyme necessary for the conversion of androgens to estrogens. If present in sufficient amounts, aromatase could catalyze the synthesis of estrogens from plasma steroid precursors and produce high breast cancer tissue concentrations. To determine the biological importance of tumor aromatase, we validated a specific and highly sensitive ³H-labeled water release assay for aromatase and used this to quantitate the amount of estrogen synthesized in vitro in breast tumors. As proof of assay validity, the [³H]water release assay detected 22.7 ± 0.09 (±sem) pmol/g h estrogen formed vs. 24.7 pmol/g-h with the direct product isolation assay. Of 61 human breast tumors studied, 48 contained measurable aromatase activity, ranging from 5–70.5 pmol estrone formed/g·h. Three aromatase inhibitors (aminoglutethimide, testololactone, and 4-hydroxyandrostenedione) blocked this activity at concentrations similar to those affecting aromatase activity in other tissues. If biologically important, the estrogen formed locally from aromatase would be expected to stimulate production of the progesterone receptor. Under these circumstances, a positive correlation of progesterone receptor and local estrogen production should be found. In contrast, no significant correlation between aromatase activity and progesterone receptor level was observed (r = –0.27; P = NS). In addition, no correlation between estrogen receptor content and aromatase activity was detected. Finally, the amount of aromatase activity present in most tumors was insufficient to produce biologically meaningful saturation of estrogen receptors. These observations suggested that aromatase, while present in the majority of breast cancer tissues, may only be biologically important in those few tumors with very high aromatase activity.