Therapeutic Ligands Antagonize Estrogen Receptor Function by Impairing Its Mobility.
Cell
; 178(4): 949-963.e18, 2019 08 08.
Article
de En
| MEDLINE
| ID: mdl-31353221
ABSTRACT
Estrogen receptor-positive (ER+) breast cancers frequently remain dependent on ER signaling even after acquiring resistance to endocrine agents, prompting the development of optimized ER antagonists. Fulvestrant is unique among approved ER therapeutics due to its capacity for full ER antagonism, thought to be achieved through ER degradation. The clinical potential of fulvestrant is limited by poor physicochemical features, spurring attempts to generate ER degraders with improved drug-like properties. We show that optimization of ER degradation does not guarantee full ER antagonism in breast cancer cells; ER "degraders" exhibit a spectrum of transcriptional activities and anti-proliferative potential. Mechanistically, we find that fulvestrant-like antagonists suppress ER transcriptional activity not by ER elimination, but by markedly slowing the intra-nuclear mobility of ER. Increased ER turnover occurs as a consequence of ER immobilization. These findings provide proof-of-concept that small molecule perturbation of transcription factor mobility may enable therapeutic targeting of this challenging target class.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Tumeurs du sein
/
Récepteurs des oestrogènes
/
Antagonistes des récepteurs des oestrogènes
/
Fulvestrant
Limites:
Animals
/
Female
/
Humans
Langue:
En
Journal:
Cell
Année:
2019
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique