2. Academic Validation
  3. CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity

CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity

  • Nat Cancer. 2021 Jan;2(1):34-48. doi: 10.1038/s43018-020-00135-y.
April C Watt 1 2,  Paloma Cejas 3 4 5,  Molly J DeCristo 6,  Otto Metzger-Filho 7,  Enid Y N Lam 1 2,  Xintao Qiu 3,  Haley BrinJones 6,  Nikolas Kesten 3,  Rhiannon Coulson 1 2,  Alba Font-Tello 3,  Klothilda Lim 3,  Raga Vadhi 3,  Veerle W Daniels 7,  Joan Montero 7 8,  Len Taing 3,  Clifford A Meyer 3,  Omer Gilan 1 2,  Charles C Bell 1 2,  Keegan D Korthauer 9 10,  Claudia Giambartolomei 11 12,  Bogdan Pasaniuc 11,  Ji-Heui Seo 3 7,  Matthew L Freedman 3 7,  Cynthia Ma 13,  Matthew J Ellis 14,  Ian Krop 7,  Eric Winer 7,  Anthony Letai 7,  Myles Brown 3 7,  Mark A Dawson 1 2 15,  Henry W Long 3 7,  Jean J Zhao 6 16 17,  Shom Goel 1 2 7
Affiliations

Affiliations

  • 1 Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 2 Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
  • 3 Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • 4 Translational Oncology Laboratory, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.
  • 5 CIBERONC CB16/12/00398, La Paz University Hospital, Madrid, Spain.
  • 6 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • 7 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • 8 Institute for Bioengineering of Catalonia, Spain.
  • 9 Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • 10 Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
  • 11 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
  • 12 Istituto Italiano di Tecnologia (IIT), Genoa, Italy.
  • 13 Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
  • 14 Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, USA.
  • 15 Centre for Cancer Research, University of Melbourne, Parkville, Victoria, Australia.
  • 16 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
  • 17 The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
PMID: 33997789 DOI: 10.1038/s43018-020-00135-y
Abstract

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) were designed to induce Cancer cell cycle arrest. Recent studies have suggested that these agents also exert other effects, influencing Cancer cell immunogenicity, apoptotic responses, and differentiation. Using cell-based and mouse models of breast Cancer together with clinical specimens, we show that CDK4/6 inhibitors induce remodeling of Cancer cell chromatin characterized by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that drive luminal differentiation and apoptotic evasion, as well as a set of enhancers overlying endogenous retroviral elements that is enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several Activator Protein-1 (AP-1) transcription factor proteins, which are in turn implicated in the activity of many of the new enhancers. Our findings offer insights into CDK4/6 pathway biology and should inform the future development of CDK4/6 inhibitors.

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