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Endocrine resistance and breast cancer plasticity are controlled by CoREST.

Authors :
Garcia-Martinez L
Adams AM
Chan HL
Nakata Y
Weich N
Stransky S
Zhang Z
Alshalalfa M
Sarria L
Mahal BA
Kesmodel SB
Celià-Terrassa T
Liu Z
Minucci S
Bilbao D
Sidoli S
Verdun RE
Morey L
Source :
Nature structural & molecular biology [Nat Struct Mol Biol] 2022 Nov; Vol. 29 (11), pp. 1122-1135. Date of Electronic Publication: 2022 Nov 07.
Publication Year :
2022

Abstract

Resistance to cancer treatment remains a major clinical hurdle. Here, we demonstrate that the CoREST complex is a key determinant of endocrine resistance and ER <superscript>+</superscript>  breast cancer plasticity. In endocrine-sensitive cells, CoREST is recruited to regulatory regions co-bound to ERα and FOXA1 to regulate the estrogen pathway. In contrast, during temporal reprogramming towards a resistant state, CoREST is recruited to AP-1 sites. In reprogrammed cells, CoREST favors chromatin opening, cJUN binding to chromatin, and gene activation by controlling SWI/SNF recruitment independently of the demethylase activity of the CoREST subunit LSD1. Genetic and pharmacological CoREST inhibition reduces tumorigenesis and metastasis of endocrine-sensitive and endocrine-resistant xenograft models. Consistently, CoREST controls a gene signature involved in invasiveness in clinical breast tumors resistant to endocrine therapies. Our studies reveal CoREST functions that are co-opted to drive cellular plasticity and resistance to endocrine therapies and tumorigenesis, thus establishing CoREST as a potential therapeutic target for the treatment of advanced breast cancer.<br /> (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Details

Language :
English
ISSN :
1545-9985
Volume :
29
Issue :
11
Database :
MEDLINE
Journal :
Nature structural & molecular biology
Publication Type :
Academic Journal
Accession number :
36344844
Full Text :
https://doi.org/10.1038/s41594-022-00856-x