Mechanisms by Which Estrogen Accelerates Ovarian Tumor Initiation.
Notice bibliographique
Résumé
Ovarian cancers present as three different types, epithelial, germ cell, and stromal, with epithelial cancers consisting ~90% of cases. As a result, it is believed that the majority of cancers that develop in the ovary arise from the ovarian surface epithelium. Previous studies have shown that exposure of mice to exogenous estradiol (E2) causes preneoplastic changes in ovarian surface epithelial (OSE) cell morphology and accelerates ovarian tumor onset. Clinically, estrogenic compounds are used for treatments such as hormone replacement therapy for relief of menopausal symptoms or as a form of contraceptive such as birth control pills. However, women using estrogen-only hormone replacement are at higher risk of ovarian cancer. Thus, the aim of this project is to determine the mechanisms by which estrogen has detrimental effects that promote an increased risk of ovarian cancer, specifically by elucidating the actions of E2 on the OSE. The pathways controlling the premalignant transformation are unknown, but exogenous E2 promote stratification and apparent loss of cellular polarity in the OSE layer. We hypothesized that this change in phenotype may be due to decreases in disabled-2 (Dab2), as Dab2 is required for epithelial cells to maintain polarity and a genome-wide screen has identified estrogen response elements in regions proximal to the transcriptional start site of Dab2 in mice and humans. Dab2 is an adaptor protein that is found in a variety of tissues and is highly expressed in breast and ovarian tissue but its expression is lost in the majority of ovarian carcinomas. To determine if Dab2 mediates the actions of E2, we examined the effects of E2 exposure on Dab2 expression (by qPCR) in cultures of normal mouse OSE (mOSE), SV40 T antigen-immortalized mOSE, and in a mouse ovarian cancer cell line (MASE). None of the cell lines showed a change in Dab2 expression in response to E2 over a range of doses (0-1000 nM) and treatment periods (0-72 hours). To determine the effects of E2 exposure on Dab2 expression in vivo, SCID mice were intraperitoneally injected with MASE cells and inserted subcutaneously with a 6o-day timed release 0.25 mg E2 pellet. Tumors showed a significant 8-fold decrease in Dab2 mRNA expression in response to E2 treatment. Tumors from the tgCAG-LS-TAg transgenic model of ovarian cancer also showed a trend for E2 suppression of Dab2 expression. Immunohistochemical detection of Dab2 shows that it is present in normal human and mouse OSE, but is lost in areas of stratified mOSE that occur at higher incidence after 60 days of exogenous E2 treatment. These results demonstrate that E2 exposure decreases Dab2 expression in both OSE and ovarian cancers in vivo, but not in vitro. The lack of response in vitro suggests that growing OSE cells on plastic is not a good model to study changes in mOSE polarity, a result that is consistent with previous studies using mammary epithelial cells. Current experiments are investigating alternative culture systems to develop a better model for the study of OSE cell polarity and epithelial cell architecture.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».