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

ABSTRACT: Endocrine therapies target the activation of the oestrogen receptor alpha (ER?) 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 (ER?) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ER? binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ER?-positive patients.

SUBMITTER: Nguyen VT 

PROVIDER: S-EPMC4674692 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature