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

Nat Commun. 2015 Nov 27:6:10044. doi: 10.1038/ncomms10044.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Aromatase Inhibitors / pharmacology
  • Aromatase Inhibitors / therapeutic use
  • Biosynthetic Pathways / drug effects
  • Biosynthetic Pathways / genetics
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cholesterol / biosynthesis*
  • Chromatin Immunoprecipitation
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Epigenesis, Genetic / genetics*
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Humans
  • Hydroxycholesterols
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Immunohistochemistry
  • In Vitro Techniques
  • MCF-7 Cells
  • Mice
  • Mice, SCID
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • Real-Time Polymerase Chain Reaction
  • Up-Regulation


  • Antineoplastic Agents, Hormonal
  • Aromatase Inhibitors
  • Estrogen Receptor alpha
  • Hydroxycholesterols
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • 27-hydroxycholesterol
  • Cholesterol