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Endocrine disorders associated with inappropriately high aromatase expression
S E Bulun1, L S Noble, K Takayama
1Cecil H. and Ida Green Center for Reproductive Biology Sciences and Department of Obstetrics-Gynecology, University of Texas Southwestern Medical Center, Dallas 75235-9051, U.S.A. Bulun@grnctr.swmed.edu
Summary
Excessive aromatase expression, the enzyme converting steroids to estrogens, is linked to various tumors and conditions like gynecomastia. This study reveals a common pathway activating aromatase expression via specific promoters in affected tissues.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Aromatase P450 (P450arom) converts C19 steroids to estrogens in multiple human tissues.
- Tissue-specific promoters regulate aromatase expression, which is typically absent in healthy adult liver, adrenal, and uterine tissues.
- Aberrant aromatase expression contributes to elevated estrogen levels, promoting hormone-responsive tissue growth.
Purpose of the Study:
- To investigate the common pathophysiological and molecular features of excessive aromatase expression in various neoplastic and non-neoplastic conditions.
- To examine aromatase expression regulation, including alternative promoter use, in disease-associated tissues.
Main Methods:
- Analysis of aromatase expression in tissue samples and cultured cells from patients with gynecomastia, various tumors (testicular, hepatic, adrenal, uterine), endometriosis, and leiomyoma.
- Studied alternative promoter utilization and regulation of aromatase expression in response to hormonal stimuli.
- Investigated the role of signaling pathways in aromatase gene transcription.
Main Results:
- Elevated aromatase activity and P450arom transcript levels were observed in diverse pathological tissues and derived cells.
- Results suggest a common metabolic abnormality involving activation of a cyclic AMP-dependent signaling pathway.
- This pathway leads to transcriptional transactivation of aromatase expression via promoters I.3 and II.
Conclusions:
- Excessive aromatase expression is a shared feature across various pathological conditions, including tumors and endocrine disorders.
- A common molecular mechanism involving cAMP signaling and specific promoter activation underlies this overexpression.
- Understanding these mechanisms may offer therapeutic targets for estrogen-dependent diseases.