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Modulation of aromatase expression in human breast tissue
1Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. schen@coh.org
The Journal of Steroid Biochemistry and Molecular Biology
|February 19, 2002
Summary
Aromatase promoter usage differs between normal breast tissue and breast tumors, involving distinct transcription factors. Environmental chemicals and treatments like aromatase inhibitors can alter aromatase activity and expression, impacting breast cancer development.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Aromatase is crucial for estrogen synthesis and breast cancer development.
- Aromatase expression is regulated by distinct promoter usage in normal breast tissue versus tumors.
- Understanding these regulatory mechanisms is key to developing effective breast cancer therapies.
Purpose of the Study:
- To elucidate the differential promoter usage of aromatase in normal and cancerous breast tissues.
- To investigate the roles of specific transcription factors in regulating aromatase expression.
- To explore how aromatase activity is modulated by therapeutic agents and environmental chemicals.
Main Methods:
- Characterization of transcription factor interactions with aromatase gene regulatory elements (promoters I.3, II, I.4, S1, CREaro).
- Analysis of changes in transcription factor expression (EAR-2, COUP-TFI, EARgamma, Snail, Slug, ERRalpha-1, CREB) in normal versus tumor tissues.
- Assessment of aromatase activity and expression following treatment with aromatase inhibitors, antiestrogen ICI 182, 780, and environmental chemicals (flavones, organochlorine pesticides).
Main Results:
- Normal breast tissue utilizes glucocorticoid-stimulated promoter I.4, while tumors use cAMP-stimulated promoters I.3 and II.
- Specific transcription factors (EAR-2, COUP-TFI, EARgamma, Snail/Slug) suppress promoters I.3/II in normal tissue, whereas others (ERRalpha-1, CREB) activate them in tumors.
- Aromatase inhibitors can paradoxically increase aromatase levels through reduced degradation and gene transcription.
- Flavones inhibit aromatase by mimicking the androgen substrate, while certain pesticides antagonize ERRalpha-1, reducing aromatase expression.
Conclusions:
- Differential promoter usage and transcription factor binding explain altered aromatase expression in breast cancer.
- Aromatase inhibitors and antiestrogens have complex effects on aromatase activity and expression.
- Environmental chemicals can modulate aromatase expression, highlighting potential endocrine disruption pathways relevant to breast cancer.