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The SEEM: selective estrogen enzyme modulators in breast cancer
J R Pasqualini1, C Ebert, G S Chetrite
1Solvay Arzncimittel, Hannover, Germany.
Abstract:
Human breast cancer tissue contains all the enzymes (estrone sulfatase, 17 beta-hydroxysteroid dehydrogenase, aromatase) involved in the last steps of estradiol biosynthesis. This tissue also contains sulfotransferase for the formation of the biologically inactive estrogen sulfates. In the past years, it has been demonstrated that various progestins (promegestone, nomegestrol acetate, medrogestone) as well as tibolone and its metabolites are potent inhibitors of sulfatase and 17 beta-hydroxysteroid dehydrogenase activities. It was also shown that medrogestone, nomegestrol acetate, promegestone or tibolone can stimulate the sulfotransferase activity for the local production of estrogen sulfates. All these data, in addition to numerous agents which can block the aromatase action, lead to the new concept of Selective Estrogen Enzyme Modulators (SEEM) which can largely apply to breast cancer tissue. The exploration of various progestins and other active agents in trials with breast cancer patients, showing an inhibitory effect on sulfatase and 17 beta-hydroxysteroid dehydrogenase, or a stimulatory effect on sulfotransferase, will provide a new option in the treatment of this disease.
Insights
Selective Estrogen Enzyme Modulators (SEEM) target key enzymes in breast cancer tissue. These agents can inhibit estradiol biosynthesis enzymes or stimulate estrogen sulfate production, offering a novel breast cancer treatment strategy.
Area of Science:
- Biochemistry
- Endocrinology
- Oncology
Background:
- Human breast cancer tissue possesses enzymes for estradiol biosynthesis and estrogen sulfate formation.
- Estradiol biosynthesis involves estrone sulfatase, 17 beta-hydroxysteroid dehydrogenase, and aromatase.
- Sulfotransferase activity leads to the production of inactive estrogen sulfates.
Purpose of the Study:
- To introduce the concept of Selective Estrogen Enzyme Modulators (SEEM) for breast cancer treatment.
- To highlight the role of specific progestins and tibolone in modulating estrogen metabolism.
- To explore novel therapeutic strategies targeting estrogen pathways in breast cancer.
Main Methods:
- Review of existing data on enzyme activities in breast cancer tissue.
- Analysis of the effects of progestins (promegestone, nomegestrol acetate, medrogestone) and tibolone on key enzymes.
- Consideration of aromatase inhibitors in conjunction with SEEM.
Main Results:
- Progestins and tibolone inhibit sulfatase and 17 beta-hydroxysteroid dehydrogenase activities.
- These agents also stimulate sulfotransferase activity, increasing estrogen sulfate production.
- Combined inhibition of biosynthesis enzymes and modulation of sulfotransferase activity is achievable.
Conclusions:
- Selective Estrogen Enzyme Modulators (SEEM) represent a new therapeutic concept for breast cancer.
- Targeting both estradiol biosynthesis and estrogen sulfate production offers a dual-action approach.
- Further clinical trials of SEEM in breast cancer patients are warranted.
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