Imperial College London
Alternate

ProfessorSimakAli

Faculty of Medicine, Department of Surgery & Cancer

Professor of Molecular Endocrine Oncology
 
 
 
//

Contact

 

+44 (0)20 7594 2811simak.ali

 
 
//

Location

 

133ICTEM buildingHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Magnani:2017:10.1038/ng.3773,
author = {Magnani, L and Frige, G and Gadaleta, RM and Corleone, G and Fabris, S and Kempe, MH and Vershure, PJ and Barozzi, I and Vircillo, V and Hong, S and Perone, Y and Saini, M and Trumpp, A and Viale, G and Neri, A and Simak, A and Colleoni, MA and Pruneri, G and Minucci, S},
doi = {10.1038/ng.3773},
journal = {Nature Genetics},
pages = {444--450},
title = {Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer},
url = {http://dx.doi.org/10.1038/ng.3773},
volume = {49},
year = {2017}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Tumor evolution is shaped by many variables, potentially involving external selective pressures induced by therapies1. After surgery, patients with estrogen receptor (ERα)-positive breast cancer are treated with adjuvant endocrine therapy2, including selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs)3. However, more than 20% of patients relapse within 10 years and eventually progress to incurable metastatic disease4. 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.
AU  - Magnani,L
AU  - Frige,G
AU  - Gadaleta,RM
AU  - Corleone,G
AU  - Fabris,S
AU  - Kempe,MH
AU  - Vershure,PJ
AU  - Barozzi,I
AU  - Vircillo,V
AU  - Hong,S
AU  - Perone,Y
AU  - Saini,M
AU  - Trumpp,A
AU  - Viale,G
AU  - Neri,A
AU  - Simak,A
AU  - Colleoni,MA
AU  - Pruneri,G
AU  - Minucci,S
DO  - 10.1038/ng.3773
EP  - 450
PY  - 2017///
SN  - 1546-1718
SP  - 444
TI  - Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer
T2  - Nature Genetics
UR  - http://dx.doi.org/10.1038/ng.3773
UR  - http://hdl.handle.net/10044/1/43545
VL  - 49
ER  -
Download