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

Nguyen, V. T. M. and Barozzi, Iros and Faronato, Monica and Lombardo, Ylenia and Steel, Jennifer H. and Győrffy, Balázs (2015) Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion. NATURE COMMUNICATIONS, 6. pp. 1-14. ISSN 2041-1723


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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
Uncontrolled Keywords: upregulation; rna transcription; RNA sequence; reverse transcription polymerase chain reaction; recurrence free survival; quantitative analysis; PHENOTYPE; overall survival; nonhuman; MOUSE; metastasis free survival; MCF 7 cell line; in vivo study; in vitro study; human cell culture; human cell; human; Histopathology; Gene Expression; epigenetics; controlled study; Chromatin structure; cholesterol synthesis; cell invasion; cancer hormone therapy; BINDING SITE; ARTICLE; animal model; animal experiment; Transcriptome; terbinafine; tamoxifen; sterol regulatory element binding protein 1; mevinolin; messenger rna; fulvestrant; Estrogen Receptor alpha; aromatase inhibitor; 26 hydroxycholesterol
Subjects: R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia
Depositing User: MTMT SWORD
Date Deposited: 04 Mar 2016 10:26
Last Modified: 04 Mar 2016 10:26

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