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Breast Cancer Research
Published in: Breast Cancer Research 1/2015

Open Access 01-12-2015 | Research article

Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer

Authors: Elena López-Knowles, Paul M Wilkerson, Ricardo Ribas, Helen Anderson, Alan Mackay, Zara Ghazoui, Aradhana Rani, Peter Osin, Ash Nerurkar, Lorna Renshaw, Alexey Larionov, William R Miller, J Michael Dixon, Jorge S Reis-Filho, Anita K Dunbier, Lesley-Ann Martin, Mitch Dowsett

Published in: Breast Cancer Research | Issue 1/2015

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Abstract

Introduction

Aromatase inhibitors (AIs) are a vital component of estrogen receptor positive (ER+) breast cancer treatment. De novo and acquired resistance, however, is common. The aims of this study were to relate patterns of copy number aberrations to molecular and proliferative response to AIs, to study differences in the patterns of copy number aberrations between breast cancer samples pre- and post-AI neoadjuvant therapy, and to identify putative biomarkers for resistance to neoadjuvant AI therapy using an integrative analysis approach.

Methods

Samples from 84 patients derived from two neoadjuvant AI therapy trials were subjected to copy number profiling by microarray-based comparative genomic hybridisation (aCGH, n = 84), gene expression profiling (n = 47), matched pre- and post-AI aCGH (n = 19 pairs) and Ki67-based AI-response analysis (n = 39).

Results

Integrative analysis of these datasets identified a set of nine genes that, when amplified, were associated with a poor response to AIs, and were significantly overexpressed when amplified, including CHKA, LRP5 and SAPS3. Functional validation in vitro, using cell lines with and without amplification of these genes (SUM44, MDA-MB134-VI, T47D and MCF7) and a model of acquired AI-resistance (MCF7-LTED) identified CHKA as a gene that when amplified modulates estrogen receptor (ER)-driven proliferation, ER/estrogen response element (ERE) transactivation, expression of ER-regulated genes and phosphorylation of V-AKT murine thymoma viral oncogene homolog 1 (AKT1).

Conclusions

These data provide a rationale for investigation of the role of CHKA in further models of de novo and acquired resistance to AIs, and provide proof of concept that integrative genomic analyses can identify biologically relevant modulators of AI response.
Appendix
Available only for authorised users
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Metadata
Title
Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer
Authors
Elena López-Knowles
Paul M Wilkerson
Ricardo Ribas
Helen Anderson
Alan Mackay
Zara Ghazoui
Aradhana Rani
Peter Osin
Ash Nerurkar
Lorna Renshaw
Alexey Larionov
William R Miller
J Michael Dixon
Jorge S Reis-Filho
Anita K Dunbier
Lesley-Ann Martin
Mitch Dowsett
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2015
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-015-0532-0

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