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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 3/2010

01-06-2010 | Preclinical study

An integrative genomic and transcriptomic analysis reveals molecular pathways and networks regulated by copy number aberrations in basal-like, HER2 and luminal cancers

Authors: Rachael Natrajan, Britta Weigelt, Alan Mackay, Felipe C. Geyer, Anita Grigoriadis, David S. P. Tan, Chris Jones, Christopher J. Lord, Radost Vatcheva, Socorro M. Rodriguez-Pinilla, Jose Palacios, Alan Ashworth, Jorge S. Reis-Filho

Published in: Breast Cancer Research and Treatment | Issue 3/2010

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Abstract

Breast cancer is a heterogeneous disease caused by the accumulation of genetic changes in neoplastic cells. We hypothesised that molecular subtypes of breast cancer may be driven by specific constellations of genes whose expression is regulated by gene copy number aberrations. To address this question, we analysed a series of 48 microdissected grade III ductal carcinomas using high resolution microarray comparative genomic hybridisation and mRNA expression arrays. There were 5,931 genes whose expression significantly correlates with copy number identified; out of these, 1,897 genes were significantly differentially expressed between basal-like, HER2 and luminal tumours. Ingenuity Pathway Analysis (IPA) revealed that ‘G1/S cell cycle regulation’ and ‘BRCA1 in DNA damage control’ pathways were significantly enriched for genes whose expression correlates with copy number and are differentially expressed between the molecular subtypes of breast cancer. IPA of genes whose expression significantly correlates with copy number in each molecular subtype individually revealed that canonical pathways involved in oestrogen receptor (ER) signalling and DNA repair are enriched for these genes. We also identified 32, 157 and 265 genes significantly overexpressed when amplified in basal-like, HER2 and luminal cancers, respectively. These lists include known and novel potential therapeutic targets (e.g. HER2 and PPM1D in HER2 cancers). Our results provide strong circumstantial evidence that different patterns of genetic aberrations in distinct molecular subtypes of breast cancer contribute to their specific transcriptomic profiles and that biological phenomena characteristic of each subtype (e.g. proliferation, HER2 and ER signalling) may be driven by specific patterns of copy number aberrations.
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Metadata
Title
An integrative genomic and transcriptomic analysis reveals molecular pathways and networks regulated by copy number aberrations in basal-like, HER2 and luminal cancers
Authors
Rachael Natrajan
Britta Weigelt
Alan Mackay
Felipe C. Geyer
Anita Grigoriadis
David S. P. Tan
Chris Jones
Christopher J. Lord
Radost Vatcheva
Socorro M. Rodriguez-Pinilla
Jose Palacios
Alan Ashworth
Jorge S. Reis-Filho
Publication date
01-06-2010
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 3/2010
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-009-0501-3

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