NDA@SZTAKI

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

RodrĂ­guez-Meira, Alba

Patten, Darren K.

Vircillo, Valentina

Periyasamy, Manikandan

Ali, Simak

Frige, Gianmaria

Minucci, Saverio

Coombes, R. Charles

Magnani, Luca

Nature Publishing Group

2015

RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkolĂłgia

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.

angol

magyar

Article

PeerReviewed

info:eu-repo/semantics/article

text

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http://real.mtak.hu/34204/1/ncomms10044.pdf

http://real.mtak.hu/34204/7/s41467-019-11569-z.pdf

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

http://real.mtak.hu/34204/

https://doi.org/10.1038/ncomms10044

MTMT:3030240; doi:10.1038/ncomms10044