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Aromatase activity in the breast and other peripheral tissues and its therapeutic regulation
D W Killinger1, E Perel, D Daniilescu
1Department of Medicine, University of Toronto, Ontario, Canada.
Abstract:
Studies using [3H]androstenedione (A) demonstrated that this substrate can be aromatized to estrone (E1) in homogenates of breast carcinoma tissue and breast adipose tissue, in breast carcinoma and breast adipose stromal cells in culture, and in cultured adipose stromal cells from sites remote from the tumor. Using cultured breast carcinoma cells, it was shown that estrogen formation was stimulated by cortisol (10(-6) M) and inhibited by endogenous 5 alpha-reduced androgens: 5 alpha-androstene-dione greater than androsterone greater than dihydrotestosterone greater than epiandrosterone greater than 3 alpha- and 3 beta- androstanediol. It was also shown that 19-nortestosterone and 19-norandrostenedione (10(-6) M) inhibited E1 formation by 80%. Progesterone (10(-6) M) had no effect on aromatase activity, while the progestational agent R5020 (10(-6) M) caused a 70% inhibition. These studies emphasize that a variety of compounds can influence aromatase activity and that drugs which are used as aromatase inhibitors in patients with breast carcinoma may have multiple sites of action.
Insights
This study shows that various compounds influence aromatase activity in breast tissue. Aromatase inhibitors used in breast cancer treatment may act on multiple targets.
Area of Science:
- Endocrinology
- Oncology
- Biochemistry
Background:
- Aromatase is crucial for estrogen synthesis, playing a role in hormone-dependent breast cancers.
- Understanding factors influencing aromatase activity is vital for developing effective breast cancer therapies.
Purpose of the Study:
- To investigate the aromatization of androstenedione to estrone in breast carcinoma and adipose tissues.
- To identify compounds that modulate aromatase activity in breast cancer cells and associated stromal cells.
Main Methods:
- Utilized [3H]androstenedione as a substrate to measure aromatase activity.
- Employed homogenates and cultured cells from breast carcinoma and adipose tissues.
- Assessed the effects of cortisol, various 5 alpha-reduced androgens, 19-norsteroids, progesterone, and R5020 on estrogen formation.
Main Results:
- Aromatization of androstenedione to estrone was confirmed in breast carcinoma and adipose tissue homogenates and cultured cells.
- Cortisol stimulated estrogen formation, while 5 alpha-reduced androgens inhibited it in a dose-dependent manner.
- 19-norsteroids and R5020 significantly inhibited estrone formation, whereas progesterone had no effect.
Conclusions:
- Aromatase activity in breast tissue is influenced by a diverse range of compounds.
- Current aromatase inhibitors used in breast cancer treatment may possess multiple mechanisms of action.
- Further research into these modulators could lead to more targeted and effective breast cancer therapies.