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Breast Cancer Research
Published in: Breast Cancer Research 1/2016

Open Access 01-12-2016 | Research article

Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer

Authors: Zhi Hu, Jian-Hua Mao, Christina Curtis, Ge Huang, Shenda Gu, Laura Heiser, Marc E. Lenburg, James E. Korkola, Nora Bayani, Shamith Samarajiwa, Jose A. Seoane, Mark A. Dane, Amanda Esch, Heidi S. Feiler, Nicholas J. Wang, Mary Ann Hardwicke, Sylvie Laquerre, Jeff Jackson, Kenneth W. Wood, Barbara Weber, Paul T. Spellman, Samuel Aparicio, Richard Wooster, Carlos Caldas, Joe W. Gray

Published in: Breast Cancer Research | Issue 1/2016

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Abstract

Background

High mitotic activity is associated with the genesis and progression of many cancers. Small molecule inhibitors of mitotic apparatus proteins are now being developed and evaluated clinically as anticancer agents. With clinical trials of several of these experimental compounds underway, it is important to understand the molecular mechanisms that determine high mitotic activity, identify tumor subtypes that carry molecular aberrations that confer high mitotic activity, and to develop molecular markers that distinguish which tumors will be most responsive to mitotic apparatus inhibitors.

Methods

We identified a coordinately regulated mitotic apparatus network by analyzing gene expression profiles for 53 malignant and non-malignant human breast cancer cell lines and two separate primary breast tumor datasets. We defined the mitotic network activity index (MNAI) as the sum of the transcriptional levels of the 54 coordinately regulated mitotic apparatus genes. The effect of those genes on cell growth was evaluated by small interfering RNA (siRNA).

Results

High MNAI was enriched in basal-like breast tumors and was associated with reduced survival duration and preferential sensitivity to inhibitors of the mitotic apparatus proteins, polo-like kinase, centromere associated protein E and aurora kinase designated GSK462364, GSK923295 and GSK1070916, respectively. Co-amplification of regions of chromosomes 8q24, 10p15-p12, 12p13, and 17q24-q25 was associated with the transcriptional upregulation of this network of 54 mitotic apparatus genes, and we identify transcription factors that localize to these regions and putatively regulate mitotic activity. Knockdown of the mitotic network by siRNA identified 22 genes that might be considered as additional therapeutic targets for this clinically relevant patient subgroup.

Conclusions

We define a molecular signature which may guide therapeutic approaches for tumors with high mitotic network activity.
Appendix
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Metadata
Title
Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer
Authors
Zhi Hu
Jian-Hua Mao
Christina Curtis
Ge Huang
Shenda Gu
Laura Heiser
Marc E. Lenburg
James E. Korkola
Nora Bayani
Shamith Samarajiwa
Jose A. Seoane
Mark A. Dane
Amanda Esch
Heidi S. Feiler
Nicholas J. Wang
Mary Ann Hardwicke
Sylvie Laquerre
Jeff Jackson
Kenneth W. Wood
Barbara Weber
Paul T. Spellman
Samuel Aparicio
Richard Wooster
Carlos Caldas
Joe W. Gray
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2016
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-016-0728-y

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