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Nat Genet. 2017 Mar;49(3):444-450. doi: 10.1038/ng.3773. Epub 2017 Jan 23.

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

Author information

1
Department of Surgery and Cancer, Imperial College London, London, UK.
2
Department of Experimental Oncology, European Institute of Oncology Milan, Italy.
3
Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, IT.
4
Swammerdam Institute for Life Sciences, University of Amsterdam.
5
Genomics Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA, USA.
6
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende (CS), Italy.
7
Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), and Institute for Stem Cell Technology and Experimental Medicine GmbH, Heidelberg, Germany.
8
Division of Pathology, European Institute of Oncology and University of Milan, School of Medicine, Milan, Italy.
9
Department of Oncology and Hemato-oncology, University of Milano, Milan, IT.
10
Division of Medical Senology, European Institute of Oncology, IEO, Milan, Italy.
11
Department of Biosciences, University of Milano, Milan, IT.
#
Contributed equally

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, CYP19A1amp cells 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 CYP19A1amp cells showing decreased sensitivity to AI treatment. These data suggest that AI treatment itself selects for acquired CYP19A1amp and promotes local autocrine estrogen signaling in AI-resistant metastatic patients.

PMID:
28112739
PMCID:
PMC5326683
DOI:
10.1038/ng.3773
[Indexed for MEDLINE]
Free PMC Article

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