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Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion

Author

Listed:
  • Van T. M. Nguyen

    (Imperial College London)

  • Iros Barozzi

    (IFOM-IEO Campus, European Institute of Oncology)

  • Monica Faronato

    (Imperial College London)

  • Ylenia Lombardo

    (Imperial College London)

  • Jennifer H. Steel

    (Imperial College London)

  • Naina Patel

    (Imperial College London)

  • Philippa Darbre

    (School of Biological Science, University of Reading)

  • Leandro Castellano

    (Imperial College London)

  • Balázs Győrffy

    (MTA TTK Lendület Cancer Biomarker Research Group, Semmelweis University
    MTA-SE Pediatrics and Nephrology Research Group, Semmelweis University)

  • Laura Woodley

    (ECMC, Charing Cross Hospital)

  • Alba Meira

    (Imperial College London)

  • Darren K. Patten

    (Imperial College London)

  • Valentina Vircillo

    (Health and Nutritional Sciences, University of Calabria)

  • Manikandan Periyasamy

    (Imperial College London)

  • Simak Ali

    (Imperial College London)

  • Gianmaria Frige

    (IFOM-IEO Campus, European Institute of Oncology)

  • Saverio Minucci

    (IFOM-IEO Campus, European Institute of Oncology)

  • R. Charles Coombes

    (Imperial College London)

  • Luca Magnani

    (Imperial College London)

Abstract

Endocrine therapies target the activation of the oestrogen receptor alpha (ERα) via distinct mechanisms, but it is not clear whether breast cancer cells can adapt to treatment using drug-specific mechanisms. Here we demonstrate that resistance emerges via drug-specific epigenetic reprogramming. Resistant cells display a spectrum of phenotypical changes with invasive phenotypes evolving in lines resistant to the aromatase inhibitor (AI). Orthogonal genomics analysis of reprogrammed regulatory regions identifies individual drug-induced epigenetic states involving large topologically associating domains (TADs) and the activation of super-enhancers. AI-resistant cells activate endogenous cholesterol biosynthesis (CB) through stable epigenetic activation in vitro and in vivo. Mechanistically, CB sparks the constitutive activation of oestrogen receptors alpha (ERα) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ERα binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ERα-positive patients.

Suggested Citation

  • Van T. M. Nguyen & Iros Barozzi & Monica Faronato & Ylenia Lombardo & Jennifer H. Steel & Naina Patel & Philippa Darbre & Leandro Castellano & Balázs Győrffy & Laura Woodley & Alba Meira & Darren K. P, 2015. "Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion," Nature Communications, Nature, vol. 6(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms10044
    DOI: 10.1038/ncomms10044
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