Epigenetic evolution of endocrine therapy resistant cells

Endocrine therapies target the activation of the estrogen 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 topological domains (TAD) 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 estrogen 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.