Endocrine resistance and breast cancer plasticity are controlled by CoREST

Liliana Garcia-Martinez, Andrew M. Adams, Ho Lam Chan, Yuichiro Nakata, Natalia Weich, Stephanie Stransky, Zhao Zhang, Mohamed Alshalalfa, Leonor Sarria, Brandon A. Mahal, Susan B. Kesmodel, Toni Celià-Terrassa, Zhijie Liu, Saverio Minucci, Daniel Bilbao, Simone Sidoli, Ramiro E. Verdun, Lluis Morey

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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+ 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.

Original languageEnglish (US)
Pages (from-to)1122-1135
Number of pages14
JournalNature Structural and Molecular Biology
Volume29
Issue number11
DOIs
StatePublished - Nov 2022

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Fingerprint

Dive into the research topics of 'Endocrine resistance and breast cancer plasticity are controlled by CoREST'. Together they form a unique fingerprint.

Cite this