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

Nguyen, Van T.M. and Barozzi, Iros and Faronato, Monica and Lombardo, Ylenia and Steel, Jennifer H. and Patel, Naina and Darbre, Philippa and Castellano, Leandro and Győrffy, Balázs and Woodley, Laura and Rodríguez-Meira, Alba and Patten, Darren K. and Vircillo, Valentina and Periyasamy, Manikandan and Ali, Simak and Frige, Gianmaria and Minucci, Saverio and 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. pp. 1-14. 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
Additional Information: Author Correction: Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion (Nature Communications, (2015), 6, 1, (10044), 10.1038/ncomms10044) Nguyen, Van T.M. és Barozzi, Iros és Faronato, Monica és Lombardo, Ylenia és Steel, Jennifer H. és Patel, Naina és Darbre, Philippa és Castellano, Leandro és Győrffy, Balázs és Woodley, Laura és Rodríguez-Meira, Alba és Patten, Darren K. és Vircillo, Valentina és Periyasamy, Manikandan és Ali, Simak és Frige, Gianmaria és Minucci, Saverio és Coombes, R. Charles és Magnani, Luca (2019) Author Correction: Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion (Nature Communications, (2015), 6, 1, (10044), 10.1038/ncomms10044). NATURE COMMUNICATIONS, 10 (1). ISSN 2041-1723 DOI: https://doi.org/10.1038/s41467-019-11569-z This Article omits a declaration from the Competing Interests statement, which should have included the following: ‘One of the authors, Y.L., is an editor on the staff of Nature Communications, but was not in any way involved in the journal review process. The other authors declare no competing interests.’ Also, the Article contains an error in the name of the author Alba Rodriguez-Meira, which is incorrectly given as Alba Meira. These errors have not been corrected in either the PDF or HTML versions of the Article. © 2019, The Author(s).
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
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 04 Mar 2016 10:26
Last Modified: 29 Nov 2019 07:50
URI: http://real.mtak.hu/id/eprint/34204

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