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

Nguyen, Van T M, Barozzi, Iros, Faronato, Monica, Lombardo, Ylenia, Steel, Jennifer H, Patel, Naina, Darbre, Philippa, Castellano, Leandro, Győrffy, Balázs, Woodley, Laura, Meira, Alba, Patten, Darren K, Vircillo, Valentina, Periyasamy, Manikandan, Ali, Simak, Frige, Gianmaria, Minucci, Saverio, Coombes, R Charles and Magnani, Luca (2015) Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion. Nature communications, 6 (10044). ISSN 2041-1723

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: Leandro Castellano
Date Deposited: 15 Jun 2018 11:31
Last Modified: 02 Jul 2019 15:30
URI: http://sro.sussex.ac.uk/id/eprint/76526

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