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SREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ERα breast cancer

Author

Listed:
  • Ylenia Perone

    (Imperial College London)

  • Aaron J. Farrugia

    (Institute of Cancer Research)

  • Alba Rodríguez-Meira

    (Imperial College London
    University of Oxford)

  • Balázs Győrffy

    (Hungarian Academy of Sciences
    Semmelweis University)

  • Charlotte Ion

    (Imperial College London)

  • Andrea Uggetti

    (European Institute of Oncology)

  • Antonios Chronopoulos

    (Imperial College London)

  • Pasquale Marrazzo

    (University of Bologna)

  • Monica Faronato

    (Imperial College London)

  • Sami Shousha

    (Charing Cross Hospital NHS Trust)

  • Claire Davies

    (Imperial College London)

  • Jennifer H. Steel

    (Imperial College London)

  • Naina Patel

    (Imperial College London)

  • Armando Rio Hernandez

    (Imperial College London)

  • Charles Coombes

    (Imperial College London)

  • Giancarlo Pruneri

    (Fondazione IRCCS Istituto Nazionale Tumori and University of Milan, School of Medicine)

  • Adrian Lim

    (Imperial College London)

  • Fernando Calvo

    (Institute of Cancer Research
    Instituto de Biomedicina y Biotecnologia de Cantabria)

  • Luca Magnani

    (Imperial College London)

Abstract

Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.

Suggested Citation

  • Ylenia Perone & Aaron J. Farrugia & Alba Rodríguez-Meira & Balázs Győrffy & Charlotte Ion & Andrea Uggetti & Antonios Chronopoulos & Pasquale Marrazzo & Monica Faronato & Sami Shousha & Claire Davies , 2019. "SREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ERα breast cancer," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09676-y
    DOI: 10.1038/s41467-019-09676-y
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