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Inhibition of endometrial carcinoma cell growth using antisense estrogen receptor oligodeoxyribonucleotides
Anthony H Taylor1, Farook al-Azzawi, J Howard Pringle
1Gynaecology Research Group, Department of Obstetrics and Gynaecology, University of Leicester, Leicester Royal Infirmary, Leicester, Leicestershire, LE2 7LX, United Kingdom.
Background:
The sex hormone 17 beta-estradiol acts as a mitogen in a number of tissues, including the endometrium, through direct interaction with the estrogen receptor (ER alpha). In the protection of the female breast and endometrium from cancer progression it would be advantageous to inhibit estrogenic action, therefore many estrogen receptor antagonists have been made. However, the most clinically relevant anti-estrogens for breast cancer have a detrimental effect on the endometrium and induce or exacerbate existing endometrial oncogenesis. Specific anti-estrogenic potential that is directed against the endometrial ER alpha theoretically could be achieved using antisense oligodeoxyribonucleotide transfection techniques.
Materials And Methods:
To discover the most effective antisense oligodeoxyribonucleotides against the human ER alpha, a series of oligodeoxyribonucleotides were synthesised and tested in a human endometrial cancer cell line that expresses a functional ER alpha.
Results:
Transfection with antisense oligodeoxyribonucleotides, directed against different regions of the human ER alpha, significantly inhibited ER alpha protein production without affecting ER beta protein levels. Antisense oligodeoxyribonucleotides directed against the translational start site demonstrated reduced binding of radiolabeled 17 beta-estradiol and a complete inhibition of estrogen-dependent endometrial cancer cell proliferation. The inhibitory effect of the antisense oligodeoxyribonucleotides on ER alpha production and ligand binding was enhanced in the presence of exogenous 17 beta-estradiol.
Conclusion:
The data suggest that antisense oligodeoxyribonucleotides against the human ER alpha have the potential of acting as anti-proliferative agents for estrogen-dependent endometrial cancers and may help in elucidating the relative roles of the two estrogen receptors, ER alpha and ER beta, in cell processes other than proliferation.
Insights
Antisense oligodeoxyribonucleotides targeting estrogen receptor alpha (ER alpha) effectively inhibit endometrial cancer cell proliferation. This approach offers a promising strategy for treating estrogen-dependent endometrial cancers without affecting ER beta.
Area of Science:
- Molecular Endocrinology
- Cancer Biology
- Oligonucleotide Therapeutics
Background:
- 17 beta-estradiol promotes endometrial cell growth via estrogen receptor alpha (ER alpha).
- Existing anti-estrogens used for breast cancer can worsen endometrial cancer.
- Targeting endometrial ER alpha specifically offers a potential therapeutic advantage.
Purpose of the Study:
- To identify effective antisense oligodeoxyribonucleotides against human ER alpha.
- To evaluate the anti-proliferative effects of these antisense agents on endometrial cancer cells.
Main Methods:
- Synthesis and testing of various antisense oligodeoxyribonucleotides against human ER alpha.
- Utilized a human endometrial cancer cell line expressing functional ER alpha.
- Assessed ER alpha protein levels, 17 beta-estradiol binding, and cell proliferation post-transfection.
Main Results:
- Antisense oligodeoxyribonucleotides significantly reduced ER alpha protein levels without impacting ER beta.
- Targeting the translational start site inhibited 17 beta-estradiol binding and estrogen-dependent proliferation.
- Exogenous 17 beta-estradiol enhanced the inhibitory effects of the antisense agents.
Conclusions:
- Antisense oligodeoxyribonucleotides against ER alpha show potential as anti-proliferative agents for endometrial cancer.
- This strategy may help differentiate the roles of ER alpha and ER beta in cellular processes.
- Further research could lead to novel treatments for estrogen-dependent gynecological cancers.