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

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.

Overexpression of kinesin superfamily members as prognostic biomarkers of breast cancer

“…KIF4A, among all six KIFs selected in our study, is the only one that functionally involved in multi-stages of mitosis, participating in chromosome condensation, anaphase spindle mid-zone formation and cytokinesis [50,62,68]. Given the hyperactive proliferation of tumor cells, overexpression of the six KIFs selected as expected, which in accordance with the results given in our study, and further demonstrations were found on both cellular and molecular levels reported in previous studies [69][70][71][72]. Tumorigenic functions of KIFs affect various aspects of breast cancer, including metastasis, progression and chemotherapy resistance.…”

“…Tumorigenic functions of KIFs affect various aspects of breast cancer, including metastasis, progression and chemotherapy resistance. Silencing of KIF10 and KIF18A were both reported inhibitions to the proliferation of breast cancer cells via deregulating cell division [20,69]. Lysosomal stability was demonstrated to enhance the survival of breast cancer cells while the knocking down of KIF20A conduced the permeabilization of the lysosomal membrane, which in turn, causing cellular death [73].…”

Integrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer

“…Identification of tumor addictions (dependence on a gene for proliferation and survival) has in the past led to the development of novel therapies, notably the discovery of ERBB2 amplification and overexpression, now targeted by a number of therapies in breast cancer 3 . Despite progress in characterizing the genomic landscape of breast cancer 4 , 5 and TNBC specifically 2 , 6 – 8 , targetable biological dependencies remain elusive and poorly characterized. With the exception of clonally dominant mutations in TP53 , TNBCs demonstrate a high degree of inter-tumor and intra-tumor heterogeneity at the mutational level with each driver mutation only present in a subset of tumors and clones within any individual tumor 9 .…”

“…Genes that are found in amplified regions and are highly expressed, may be drivers of important “hallmarks” of malignancy 11 and potentially represent essential tumor addictions. A number of high-throughput loss of function screening studies have identified gene addictions in cellular models of cancer including breast cancer models 4 , 5 , 12 but functional validation has been limited and studies have rarely been informed by evidence of upregulation of gene copy number or mRNA in large numbers of patient tumors. Therefore, the main aim of this study is to identify and validate recurrently amplified genes as being important for malignant phenotypes in TNBC.…”

Personalized Cancer Care: Risk Prediction, Early Diagnosis, Progression, and Therapy

“…He stated that it is necessary to make links between functional oncogene signatures of cancer subsets and combinations of drugs that can be used to guide the treatment of individual patients to improved outcomes and decreased toxicity [17] . Joe Gray gave an example of large-scale drug screening by defining a molecular signature, which may guide therapeutic approaches for tumors with high mitotic network activity [18] . This approach is supported by Seashore-Ludlow et al [19] who developed a novel annotated cluster multidimensional enrichment analysis to explore the association between groups of small molecules and groups of cancer cell lines in a new, quantitative, sensitive data set.…”