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

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

doi:10.1186/s13058-016-0728-y

Abstract

BackgroundHigh 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.MethodsWe 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).ResultsHigh 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.ConclusionsWe define a molecular signature which may guide therapeutic approaches for tumors with high mitotic network activity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0728-y) contains supplementary material, which is available to authorized users.

Highlights

High mitotic activity is associated with the genesis and progression of many cancers
As germline polymorphisms associated with aspects of cancer genesis and/ or progression are sometimes enhanced in tumors by selection of genomic aberrations that further alter transcription of the target genes [15,16,17], we investigated the possibility that the high mitotic network activity characteristic of aggressive breast cancer is influenced by genomic aberrations that accumulate during breast cancer genesis and progression
We show that breast cancer cell lines with high mitotic activity are preferentially sensitive to small molecule inhibitors that target mitotic apparatus proteins PLK1, centromere associated protein E (CENPE) and AURKB/C, designated GSK462364 [18, 19], GSK923295 [13, 20], and GSK1070916 [21, 22], respectively

Summary

Introduction

High mitotic activity is associated with the genesis and progression of many cancers. 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. As high mitotic activity is associated with the genesis and progression of many cancers, small molecule inhibitors of mitotic apparatus proteins are being developed and evaluated clinically as anticancer agents [5,6,7,8,9,10]. With clinical trials of several of these experimental compounds commencing, it is important to understand the molecular mechanisms that determine high mitotic activity, identify tumor subtypes that harbor molecular aberrations that confer high mitotic activity, and to develop molecular markers that define tumors that will be most responsive to mitotic apparatus inhibitors. It is important to understand how mitotic apparatus protein inhibitors interact in order to guide combined therapeutic strategies

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Discussion

Conclusion