Endonuclease FEN1 Coregulates ERα Activity and Provides a Novel Drug Interface in Tamoxifen-Resistant Breast Cancer.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 05 2020
15 05 2020
Historique:
received:
17
07
2019
revised:
30
01
2020
accepted:
09
03
2020
pubmed:
21
3
2020
medline:
27
10
2020
entrez:
21
3
2020
Statut:
ppublish
Résumé
Estrogen receptor α (ERα) is a key transcriptional regulator in the majority of breast cancers. ERα-positive patients are frequently treated with tamoxifen, but resistance is common. In this study, we refined a previously identified 111-gene outcome prediction-classifier, revealing FEN1 as the strongest determining factor in ERα-positive patient prognostication. FEN1 levels were predictive of outcome in tamoxifen-treated patients, and FEN1 played a causal role in ERα-driven cell growth. FEN1 impacted the transcriptional activity of ERα by facilitating coactivator recruitment to the ERα transcriptional complex. FEN1 blockade induced proteasome-mediated degradation of activated ERα, resulting in loss of ERα-driven gene expression and eradicated tumor cell proliferation. Finally, a high-throughput 465,195 compound screen identified a novel FEN1 inhibitor, which effectively blocked ERα function and inhibited proliferation of tamoxifen-resistant cell lines as well as
Identifiants
pubmed: 32193286
pii: 0008-5472.CAN-19-2207
doi: 10.1158/0008-5472.CAN-19-2207
doi:
Substances chimiques
Antineoplastic Agents, Hormonal
0
ESR1 protein, human
0
Estrogen Receptor alpha
0
Tamoxifen
094ZI81Y45
Flap Endonucleases
EC 3.1.-
FEN1 protein, human
EC 3.1.11.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1914-1926Informations de copyright
©2020 American Association for Cancer Research.