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Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer

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Title: Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer
Authors: Magnani, L
Frige, G
Gadaleta, RM
Corleone, G
Fabris, S
Kempe, MH
Vershure, PJ
Barozzi, I
Vircillo, V
Hong, S
Perone, Y
Saini, M
Trumpp, A
Viale, G
Neri, A
Simak, A
Colleoni, MA
Pruneri, G
Minucci, S
Item Type: Journal Article
Abstract: Tumor evolution is shaped by many variables , potentially involving external selective pressures induced by therapies 1 . After surgery, e strogen receptor (ERα) positive breast cancer (BCa) patients are treated with adjuvant endocrine therapy 2 includ ing selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs) 3 . However, over 20% of patients relapse within 10 years and eventually progress to incurable metastatic disease 4 . Here we demonstrate that the choice of therapy has a fundamental influence on the genetic landscape of relapse d disease s: in this study , 21.5% of AI-treated , relapsed patients had acquire d CYP19A1 gene (aromatase) amplification ( CYP19A1 amp ). Relapsed patients also developed numerous mutations targeting key breast cancer genes including ESR1 and CYP19A1 . Strikingly, CYP19A1 amp cells also emerge in vitro but only in AI resistant models . CYP19A1 amplifi cation causes increased aromatase activity and estrogen-independent ERα binding to target genes result ing in CYP19A1 amp cells display ing decrea sed sensitivity to AI treatment . Collectively these data suggest that AI treatment itself selects for acquired CYP19A1 amplification and promotes local autocrine estrogen signalling in AI resistant metastatic patients.
Issue Date: 23-Jan-2017
Date of Acceptance: 18-Nov-2016
URI: http://hdl.handle.net/10044/1/43545
DOI: https://dx.doi.org/10.1038/ng.3773
ISSN: 1546-1718
Publisher: Nature Publishing Group
Start Page: 444
End Page: 450
Journal / Book Title: Nature Genetics
Volume: 49
Copyright Statement: © 2017 Nature Publishing Group.
Sponsor/Funder: Commission of the European Communities
Imperial College London
Funder's Grant Number: 642691
Junior research Fellowship 2012/2013
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
ANDROGEN RECEPTOR GENE
PROSTATE-CANCER
LIGAND-BINDING
ESR1 MUTATIONS
PROGRESSION
EVOLUTION
REVEALS
GENOME
CELLS
Developmental Biology
11 Medical And Health Sciences
06 Biological Sciences
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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