TY - JOUR
T1 - Endocrine resistance and breast cancer plasticity are controlled by CoREST
AU - Garcia-Martinez, Liliana
AU - Adams, Andrew M.
AU - Chan, Ho Lam
AU - Nakata, Yuichiro
AU - Weich, Natalia
AU - Stransky, Stephanie
AU - Zhang, Zhao
AU - Alshalalfa, Mohamed
AU - Sarria, Leonor
AU - Mahal, Brandon A.
AU - Kesmodel, Susan B.
AU - Celià-Terrassa, Toni
AU - Liu, Zhijie
AU - Minucci, Saverio
AU - Bilbao, Daniel
AU - Sidoli, Simone
AU - Verdun, Ramiro E.
AU - Morey, Lluis
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/11
Y1 - 2022/11
N2 - 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+ 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.
AB - 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+ 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.
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U2 - 10.1038/s41594-022-00856-x
DO - 10.1038/s41594-022-00856-x
M3 - Article
C2 - 36344844
AN - SCOPUS:85141410689
SN - 1545-9993
VL - 29
SP - 1122
EP - 1135
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 11
ER -
