2. Academic Validation
  3. Endocrine resistance and breast cancer plasticity are controlled by CoREST

Endocrine resistance and breast cancer plasticity are controlled by CoREST

  • Nat Struct Mol Biol. 2022 Nov 7. doi: 10.1038/s41594-022-00856-x.
Liliana Garcia-Martinez 1 2,  Andrew M Adams 1 2,  Ho Lam Chan 1 2,  Yuichiro Nakata 1 2,  Natalia Weich 1 3,  Stephanie Stransky 4,  Zhao Zhang 5,  Mohamed Alshalalfa 1,  Leonor Sarria 1 2,  Brandon A Mahal 1,  Susan B Kesmodel 1 6,  Toni Celià-Terrassa 7,  Zhijie Liu 5,  Saverio Minucci 8 9,  Daniel Bilbao 1,  Simone Sidoli 4,  Ramiro E Verdun 10 11,  Lluis Morey 12 13
Affiliations

Affiliations

  • 1 Sylvester Comprehensive Cancer Center, Miami, FL, USA.
  • 2 Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 3 Division of Hematology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 4 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 5 Department of Molecular Medicine, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
  • 6 Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 7 Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
  • 8 Department of Experimental Oncology, European Institute of Oncology (IEO), IRCCS, Milan, Italy.
  • 9 Department of Biosciences, University of Milan, Milan, Italy.
  • 10 Sylvester Comprehensive Cancer Center, Miami, FL, USA. rverdun@med.miami.edu.
  • 11 Division of Hematology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA. rverdun@med.miami.edu.
  • 12 Sylvester Comprehensive Cancer Center, Miami, FL, USA. lmorey@med.miami.edu.
  • 13 Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA. lmorey@med.miami.edu.
PMID: 36344844 DOI: 10.1038/s41594-022-00856-x
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.

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