title: Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer.
abstract: Tumor evolution is shaped by many variables, potentially involving external selective pressures induced by therapies. After surgery, patients with estrogen receptor (ERα)-positive breast cancer are treated with adjuvant endocrine therapy, including selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs). However, more than 20% of patients relapse within 10 years and eventually progress to incurable metastatic disease. Here we demonstrate that the choice of therapy has a fundamental influence on the genetic landscape of relapsed diseases. We found that 21.5% of AI-treated, relapsed patients had acquired CYP19A1 (encoding aromatase) amplification (CYP19A1amp). Relapsed patients also developed numerous mutations targeting key breast cancer-associated genes, including ESR1 and CYP19A1. Notably, CYP19A1ampcells also emerged in vitro, but only in AI-resistant models. CYP19A1 amplification caused increased aromatase activity and estrogen-independent ERα binding to target genes, resulting in CYP19A1ampcells showing decreased sensitivity to AI treatment. These data suggest that AI treatment itself selects for acquired CYP19A1ampand promotes local autocrine estrogen signaling in AI-resistant metastatic patients.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Luca
authors.initials: L
authors.lastname: Magnani
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology Milan, Italy.
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Frige
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Raffaella Maria
authors.initials: RM
authors.lastname: Gadaleta
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Corleone
authors.affiliation: Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, IT.
authors.forename: Sonia
authors.initials: S
authors.lastname: Fabris
authors.affiliation: Swammerdam Institute for Life Sciences, University of Amsterdam.
authors.forename: Mannus H
authors.initials: MH
authors.lastname: Kempe
authors.affiliation: Swammerdam Institute for Life Sciences, University of Amsterdam.
authors.forename: Pernette J
authors.initials: PJ
authors.lastname: Verschure
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA, USA.
authors.forename: Iros
authors.initials: I
authors.lastname: Barozzi
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende (CS), Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vircillo
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Sung-Pil
authors.initials: SP
authors.lastname: Hong
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Ylenia
authors.initials: Y
authors.lastname: Perone
authors.affiliation: Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and Institute for Stem Cell Technology and Experimental Medicine GmbH, Heidelberg, Germany.
authors.forename: Massimo
authors.initials: M
authors.lastname: Saini
authors.affiliation: Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and Institute for Stem Cell Technology and Experimental Medicine GmbH, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.affiliation: Division of Pathology, European Institute of Oncology and University of Milan, School of Medicine, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.affiliation: Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, IT.|Department of Oncology and Hemato-oncology, University of Milano, Milan, IT.
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Simak
authors.initials: S
authors.lastname: Ali
authors.affiliation: Division of Medical Senology, European Institute of Oncology, IEO, Milan, Italy.
authors.forename: Marco Angelo
authors.initials: MA
authors.lastname: Colleoni
authors.affiliation: Division of Pathology, European Institute of Oncology and University of Milan, School of Medicine, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pruneri
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology Milan, Italy.|Department of Biosciences, University of Milano, Milan, IT.
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001141:Aromatase / Q000235:genetics*; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000235:genetics
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D047628:Estrogen Receptor alpha; D001141:Aromatase; C561410:CYP19A1 protein, human