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Open Access 01-04-2012 | Research article

Functional characterization of the 19q12 amplicon in grade III breast cancers

Authors: Rachael Natrajan, Alan Mackay, Paul M Wilkerson, Maryou B Lambros, Daniel Wetterskog, Monica Arnedos, Kai-Keen Shiu, Felipe C Geyer, Anita Langerød, Bas Kreike, Fabien Reyal, Hugo M Horlings, Marc J van de Vijver, Jose Palacios, Britta Weigelt, Jorge S Reis-Filho

Published in: Breast Cancer Research | Issue 2/2012

Abstract

Introduction

The 19q12 locus is amplified in a subgroup of oestrogen receptor (ER)-negative grade III breast cancers. This amplicon comprises nine genes, including cyclin E1 (CCNE1), which has been proposed as its 'driver'. The aim of this study was to identify the genes within the 19q12 amplicon whose expression is required for the survival of cancer cells harbouring their amplification.

Methods

We investigated the presence of 19q12 amplification in a series of 313 frozen primary breast cancers and 56 breast cancer cell lines using microarray comparative genomic hybridisation (aCGH). The nine genes mapping to the smallest region of amplification on 19q12 were silenced using RNA interference in phenotypically matched breast cancer cell lines with (MDA-MB-157 and HCC1569) and without (Hs578T, MCF7, MDA-MB-231, ZR75.1, JIMT1 and BT474) amplification of this locus. Genes whose silencing was selectively lethal in amplified cells were taken forward for further validation. The effects of cyclin-dependent kinase 2 (CDK2) silencing and chemical inhibition were tested in cancer cells with and without CCNE1 amplification.

Results

19q12 amplification was identified in 7.8% of ER-negative grade III breast cancer. Of the nine genes mapping to this amplicon, UQCRFS1, POP4, PLEKHF1, C19ORF12, CCNE1 and C19ORF2 were significantly over-expressed when amplified in primary breast cancers and/or breast cancer cell lines. Silencing of POP4, PLEKHF1, CCNE1 and TSZH3 selectively reduced cell viability in cancer cells harbouring their amplification. Cancer cells with CCNE1 amplification were shown to be dependent on CDK2 expression and kinase activity for their survival.

Conclusions

The 19q12 amplicon may harbour more than a single 'driver', given that expression of POP4, PLEKHF1, CCNE1 and TSZH3 is required for the survival of cancer cells displaying their amplification. The observation that cancer cells harbouring CCNE1 gene amplification are sensitive to CDK2 inhibitors provides a rationale for the testing of these chemical inhibitors in a subgroup of patients with ER-negative grade III breast cancers.

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Title: Functional characterization of the 19q12 amplicon in grade III breast cancers
Authors: Rachael Natrajan
Alan Mackay
Paul M Wilkerson
Maryou B Lambros
Daniel Wetterskog
Monica Arnedos
Kai-Keen Shiu
Felipe C Geyer
Anita Langerød
Bas Kreike
Fabien Reyal
Hugo M Horlings
Marc J van de Vijver
Jose Palacios
Britta Weigelt
Jorge S Reis-Filho
Publication date: 01-04-2012
Publisher: BioMed Central
Published in: Breast Cancer Research / Issue 2/2012
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/bcr3154

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In vivo breast cancer characterization imaging using two monoclonal antibodies activatably labeled with near infrared fluorophores

Keynote webinar | Spotlight on antibody–drug conjugates in cancer