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

Nguyen Van T. M., Iros Barozzi, Monica Faronato, Ylenia Lombardo, Jennifer H. Steel, Naina Patel, Philippa Darbre, Leandro Castellano, Balázs Győrffy, Laura Woodley, Alba Meira, Darren K. Patten, Valentina Vircillo, Manikandan Periyasamy, Simak Ali, Gianmaria Frige, Saverio Minucci, R. Charles Coombes and Luca Magnani ()
Additional contact information
Nguyen Van T. M.: 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
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

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms10044

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