Egyszerű nézet Nguyen VTM Barozzi I Faronato M Lombardo Y Steel JH Patel N Darbre P Castellano L Győrffy B Woodley L Meira A Patten DK Vircillo V Periyasamy M Ali S Frige G Minucci S Coombes RC Magnani L 2019-01-10T09:02:20Z 2019-01-10T09:02:20Z 2015
dc.identifier 84948679022
dc.identifier journalVolume=6;journalTitle=NATURE COMMUNICATIONS;journalAbbreviatedTitle=NAT COMMUN;
dc.identifier.citation pagination=10044, pages: 14; journalVolume=6; journalTitle=NATURE COMMUNICATIONS;
dc.identifier.uri doi:10.1038/ncomms10044
dc.description.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.
dc.relation.ispartof urn:issn:2041-1723
dc.title Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion 2018-12-18T09:41:24Z
dc.rights.holder NULL
dc.identifier.mtmt 3030240
dc.identifier.wos 000366376100001
dc.identifier.pubmed 26610607
dc.contributor.department SE/AOK/K/II. Sz. Gyermekgyógyászati Klinika
dc.contributor.department MTA-SE Gyermekgyógyászati és Nephrológiai Kutatócsoport
dc.contributor.department Onkológiai Biomarker Kutatócsoport (Lendület)
dc.contributor.institution Enzimológiai Intézet

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