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

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posted on 2023-06-09, 13:47 authored by Van T M Nguyen, Iros Barozzi, Monica Faronato, Ylenia Lombardo, Jennifer H Steel, Naina Patel, Philippa Darbre, Leandro CastellanoLeandro Castellano, Balázs Gyorffy, Laura Woodley, Alba Meira, Darren K Patten, Valentina Vircillo, Manikandan Periyasamy, Simak Ali, Gianmaria Frige, Saverio Minucci, R Charles Coombes, Luca Magnani
Endocrine therapies target the activation of the oestrogen receptor alpha (ERa) 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 (ERa) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ERa binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ERa-positive patients.

History

Publication status

  • Published

File Version

  • Published version

Journal

Nature Communications

ISSN

2041-1723

Publisher

Nature Research

Issue

10044

Volume

6

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-06-15

First Open Access (FOA) Date

2018-06-15

First Compliant Deposit (FCD) Date

2018-06-15

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