Abstract 2114: UGT2B17 is a unique co-regulator of the androgen receptor and androgen receptor splice variants in prostate cancer
Notice bibliographique
Résumé
Abstract Background: Expression of the steroid glucuronidating enzyme, UGT2B17, is suppressed by ligand bound full-length androgen receptor (AR-FL). However, we have shown that the AR constitutively active AR splice variants AR-V7 and ARv567es significantly increase the expression of UGT2B17 in prostate cancer cell lines and xenografts. Further, recent studies demonstrated that UGT2B17 is increased in patients with castrate recent prostate cancer. We have also shown that UGT2B17 is increased in multiple cell lines when AR splice variants (AR-Vs) increase in response to androgen deprivation therapies such as enzalutamide and abiraterone. Objective: Since UGT2B17 functions to glucuronidate dihydrotestosterone (DHT) and decrease intracellular androgen, it would be a potential mechanism for generation of constitutively active AR-Vs by androgen deprivation therapy-induced alternative splicing. In xenografts that have been shown to harbor genomic rearrangements that encode for AR-Vs, we see marked elevations of UGT2B17, an indication that it was not necessary for generation of AR-Vs but has additional activities to enhance AR-Vs signaling. The purpose of this study was to determine the interaction of UGT2B17 with AR-Vs, in cell lines that have not been shown to harbor AR genomic rearrangements. Results: In the parental LNCaP cell line, expression of UGT2B17 decreased after growth in charcoal stripped serum (CSS) supplemented with 10-9M DHT. Expression increased following growth in CSS alone and when enzalutamide was added to CSS. In contrast, in LNCaP-abl or LNCaP 95 cells, which are castration resistant sublines that express AR-Vs, basal UGT2B17 was significantly elevated compared with LNCaP baseline levels. Further, in these castrate resistant sublines, UGT2B17 exhibited less suppression by DHT and there was no increase in UGTB17 over baseline following enzalutamide treatment. ChIP assays in parental LNCaP cells stably transfected with ARv567es demonstrated binding to the UGT2B17 promoter in the absence of DHT and decreased binding in the presence of DHT. In control LNCaP cells transfected with empty vector, no binding to the UGT2B17 promoter was seen in the presence of DHT. Similar results were seen in enzalutamide resistant VCaP xenografts: UGT2B17 was elevated in the castrated state but suppressed when DHT was added. When lysates from LNCaP-abl, LNCaP 95, or VCaP cells grown in CSS were immunoprecipitated with UGT2B17 antibody then blotted with an AR-N terminal antibody, AR and AR-Vs were noted to be present. AR-negative M12 cells and LNCaP cells grown in DHT demonstrated no pull-down of AR in the UGT2B17 IP's. Interpretation: This study demonstrated that UGT2B17 is a unique co-regulator of AR-Vs activity and it is up-regulated by AR-Vs and suppressed by androgen transactivated AR-FL receptor. UGT2B17 may thus be part of an autocrine-loop driving castrate resistant prostate cancer by AR-Vs. Citation Format: Gang Liu, Shihua Sun, Kathleen Haugk, Cynthia Sprenger, Xeusen Dong, Elahe Mostaghel, Stephen R. Plymate. UGT2B17 is a unique co-regulator of the androgen receptor and androgen receptor splice variants in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2114. doi:10.1158/1538-7445.AM2014-2114
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| 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) | 0,003 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».