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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number10044
JournalNature Communications
Volume6
DOIs
Publication statusPublished - Nov 27 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

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