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

• Published in: Molecular human reproduction Vol. 10; no. 12; pp. 853 - 860
• Main Authors: Oehler, Martin K., Greschik, Holger, Fischer, Dagmar-C., Tong, Xiaowen, Schuele, Roland, Kieback, Dirk G.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.12.2004
• Subjects: adenomyosis uteri; Amino Acid Substitution; Animals; Biological and medical sciences; Cell Line; DNA-Binding Proteins - drug effects; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Electrophoretic Mobility Shift Assay; Embryology: invertebrates and vertebrates. Teratology; endometriosis; Endometriosis - genetics; Endometriosis - metabolism; Estrogen Receptor alpha - drug effects; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - physiology; Female; Fundamental and applied biological sciences. Psychology; human estrogen receptor alpha; Humans; Point Mutation - genetics; Protein Structure, Secondary - genetics; Protein Structure, Tertiary - genetics; somatic mutation; steroid receptor; Transcription, Genetic; Transfection; Uterine Diseases - genetics; Uterine Diseases - metabolism; Characterization; Human; Somatic mutation; Estrogen receptor α; Estrogen receptor; adenomyosis uteri/endometriosis/human estrogen receptor alpha/somatic mutation/steroid receptor; Uterine diseases; Endometriosis; Steroid hormone receptor; Female genital diseases; Hormonal receptor
• DOI: 10.1093/molehr/gah113
• ISSN: 1360-9947

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) α gene mutations in three out of 55 samples from adenomyosis uteri. Functional characterization revealed that two of the mutant ERα 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.