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
  • 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. [email protected].
  • 11. Division of Hematology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA. [email protected].
  • 12. Sylvester Comprehensive Cancer Center, Miami, FL, USA. [email protected].
  • 13. Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA. [email protected].
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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