Functional characterization of somatic point mutations of the human estrogen receptor α (hERα) in adenomyosis uteri

Martin K Oehler, Holger Greschik, Dagmar-C Fischer, Dagmar‐C. Fischer, Xiaowen Tong, Roland Schuele, Dirk G Kieback, D. G. Kieback
Molecular human reproduction · 2004 · vol. 10(12) , pp. 853–860 · doi:10.1093/molehr/gah113 · PMID:15475371 · W2113078874
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Somatic point mutations in the human estrogen receptor alpha gene were identified in adenomyosis uteri, with two mutants showing impaired DNA-binding and transactivation, potentially explaining resistance to hormonal therapy.

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Abstract

Endometriosis and adenomyosis uteri are chronic, benign diseases caused by the presence of endometrial tissue in ectopic locations, e.g. peritoneal or deep inside the myometrial wall of the uterus and/or in the rectovaginal septum. Although adenomyosis might be considered as a special form of endometriosis, both conditions differ with respect to clinical symptoms and treatment. Induction of a hypo-estrogenic state alone or in combination with surgical removal of the extra-uterine lesion is mostly sufficient for treatment of peritoneal endometriosis. By contrast, adenomyosis uteri rarely responds to hormonal therapy and usually requires a hysterectomy for cure. Consequently, the role of steroid hormone receptors with respect to the aetiology of either condition is still a matter of discussion. Using PCR/single strand conformation polymorphism analysis, we identified somatic estrogen receptor (ER) alpha gene mutations in three out of 55 samples from adenomyosis uteri. Functional characterization revealed that two of the mutant ERalpha proteins display severely impaired DNA-binding and transactivation properties secondary to an altered response to estrogens or changes in epidermal growth factor-mediated ligand-independent activation. Although the exact mechanism remains unknown, we suggest that mutation-related silencing of estrogen responsiveness might render endometriotic cells resistant to hypo-estrogenic conditions thereby accounting for failure of estrogen-ablative therapy in adenomyosis.

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Condition tags

mesh:D004715endometriosisadenomyosis

MeSH descriptors

Endometriosis Estrogen Receptor alpha Point Mutation Uterine Diseases Amino Acid Substitution Animals Cell Line DNA-Binding Proteins DNA-Binding Proteins DNA-Binding Proteins DNA-Binding Proteins Electrophoretic Mobility Shift Assay Endometriosis Endometriosis Estrogen Receptor alpha Estrogen Receptor alpha Estrogen Receptor alpha Female Humans Point Mutation

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References (47)

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