title: 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 (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.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Van T M
authors.initials: VT
authors.lastname: Nguyen
authors.affiliation: IFOM-IEO Campus, European Institute of Oncology, Milan 20139, Italy.
authors.forename: Iros
authors.initials: I
authors.lastname: Barozzi
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Monica
authors.initials: M
authors.lastname: Faronato
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Ylenia
authors.initials: Y
authors.lastname: Lombardo
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Steel
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Naina
authors.initials: N
authors.lastname: Patel
authors.affiliation: School of Biological Science, University of Reading, Reading RG6 6LA, UK.
authors.forename: Philippa
authors.initials: P
authors.lastname: Darbre
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Leandro
authors.identifier: http://orcid.org/0000-0002-3059-4829
authors.initials: L
authors.lastname: Castellano
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, 2nd Department of Pediatrics, Semmelweis University, Budapest H-1117, Hungary.|MTA-SE Pediatrics and Nephrology Research Group, 2nd Department of Pediatrics, Semmelweis University, Budapest H-1117, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: ECMC, Charing Cross Hospital, London W120nn, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Woodley
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Alba
authors.initials: A
authors.lastname: Meira
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Darren K
authors.initials: DK
authors.lastname: Patten
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende (CS) 87036, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vircillo
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Periyasamy
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Simak
authors.identifier: http://orcid.org/0000-0002-1320-0816
authors.initials: S
authors.lastname: Ali
authors.affiliation: IFOM-IEO Campus, European Institute of Oncology, Milan 20139, Italy.
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Frige
authors.affiliation: IFOM-IEO Campus, European Institute of Oncology, Milan 20139, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Luca
authors.identifier: http://orcid.org/0000-0002-7534-0785
authors.initials: L
authors.lastname: Magnani
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D053898:Biosynthetic Pathways / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002784:Cholesterol / Q000096:biosynthesis*; D047369:Chromatin Immunoprecipitation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D047628:Estrogen Receptor alpha; D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C076996:27-hydroxycholesterol; D002784:Cholesterol