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

Nguyen, V. T.M., Barozzi, I., Faronata, M., Lombardo, Y., Steel, J. H., Patel, N., Darbre, P., Castellano, L., Gyorffy, B., Woodley, L., Rodriguez-Meira, A., Patten, D. K., Vircillo, V., Periyasamy, M., Ali, S., Frige, G., Minucci, S., Coombes, R. C. and Magnani, L. (2015) Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion. Nature Communications, 6. 10044. ISSN 2041-1723 doi: 10.1038/ncomms10044

Abstract/Summary

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

Additional Information	Related URL is for author correction published 06/08/2019.
Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/48345
Item Type	Article
Refereed	Yes
Divisions	Life Sciences > School of Biological Sciences > Biomedical Sciences
Additional Information	Related URL is for author correction published 06/08/2019.
Publisher	Nature Publishing Group
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