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 - Funding Information:
We are indebted to members of the Morey laboratory for discussions and to the Oncogenomics Core Facility, Cancer Modeling Shared Resource, and Flow Cytometry Core Facility at the Sylvester Comprehensive Cancer Center (SCCC). T47D-ERαY537Scells were kindly provided by S. Oesterreich (University of Pittsburgh). This work was supported by SCCC funds to L. M. and R. E. V., the Florida Health Bankhead-Coley Cancer Research Program (20B15), the V Foundation (DEC2020-009), the Lampert Breast Cancer Research Fund, and R01GM141349 from the National Institute of General Medical Sciences to L. M., and R01GM121595 from the National Institute of General Medical Sciences and 1R01CA233945 from the National Cancer Institute to R. E. V. Research in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number P30CA240139. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
We are indebted to members of the Morey laboratory for discussions and to the Oncogenomics Core Facility, Cancer Modeling Shared Resource, and Flow Cytometry Core Facility at the Sylvester Comprehensive Cancer Center (SCCC). T47D-ERα cells were kindly provided by S. Oesterreich (University of Pittsburgh). This work was supported by SCCC funds to L. M. and R. E. V., the Florida Health Bankhead-Coley Cancer Research Program (20B15), the V Foundation (DEC2020-009), the Lampert Breast Cancer Research Fund, and R01GM141349 from the National Institute of General Medical Sciences to L. M., and R01GM121595 from the National Institute of General Medical Sciences and 1R01CA233945 from the National Cancer Institute to R. E. V. Research in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number P30CA240139. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Y537S
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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UR - http://www.scopus.com/inward/citedby.url?scp=85141410689&partnerID=8YFLogxK
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 -
